Impaired Inhibitory Control of Saccadic Eye Movements in Cervical Dystonia: An Eye-Tracking Study.

BACKGROUND: The pathophysiology of cervical dystonia is still unclear. Recent evidence points toward a network disorder affecting several brain areas. The objective of this study was to assess the saccadic inhibition as a marker of corticostriatal function in cervical dystonia. METHODS: We recruited 31 cervical dystonia patients and 17 matched healthy controls. Subjects performed an overlap prosaccade, an antisaccade, and a countermanding task on an eye tracker to assess automatic visual response and response inhibition. RESULTS: Cervical dystonia patients made more premature saccades (P = 0.041) in the overlap prosaccade task and more directional errors in the antisaccade task (P = 0.011) and had a higher rate of failed inhibition in the countermanding task (P = 0.001). CONCLUSIONS: The results suggest altered saccadic inhibition in cervical dystonia, possibly as a consequence of dysfunctional corticostriatal networks. Further studies are warranted to confirm whether these abnormalities are affected by the available therapies and whether this type of impairment is found in other focal dystonias. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Propentdyopents as Heme Degradation Intermediates Constrict Mouse Cerebral Arterioles and Are Present in the Cerebrospinal Fluid of Patients With Subarachnoid Hemorrhage.

RATIONALE: Delayed ischemic neurological deficit is the most common cause of neurological impairment and unfavorable prognosis in patients with subarachnoid hemorrhage (SAH). Despite the existence of neuroimaging modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed perfusion deficit. Previous studies have suggested that BOXes (bilirubin oxidation end products), originating from released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction. Recently, isolated intermediates of oxidative bilirubin degradation, known as PDPs (propentdyopents), have been considered as potential additional effectors in the development of arterial vasoconstriction. OBJECTIVE: To investigate whether PDPs and BOXes are present in hemorrhagic cerebrospinal fluid and involved in the vasoconstriction of cerebral arterioles. METHODS AND RESULTS: Via liquid chromatography/mass spectrometry, we measured increased PDP and BOX concentrations in cerebrospinal fluid of SAH patients compared with control subjects. Using differential interference contrast microscopy, we analyzed the vasoactivity of PDP isomers in vitro by monitoring the arteriolar diameter in mouse acute brain slices. We found an arteriolar constriction on application of PDPs in the concentration range that occurs in the cerebrospinal fluid of patients with SAH. By imaging arteriolar diameter changes using 2-photon microscopy in vivo, we demonstrated a short-onset vasoconstriction after intrathecal injection of either PDPs or BOXes. Using magnetic resonance imaging, we observed a long-term PDP-induced delay in cerebral perfusion. For all conditions, the arteriolar narrowing was dependent on functional big conductance potassium channels and was absent in big conductance potassium channels knockout mice. CONCLUSIONS: For the first time, we have quantified significantly higher concentrations of PDP and BOX isomers in the cerebrospinal fluid of patients with SAH compared to controls. The vasoconstrictive effect caused by PDPs in vitro and in vivo suggests a hitherto unrecognized pathway contributing to the pathogenesis of delayed ischemic deficit in patients with SAH.

Do emotional stimuli interfere with response inhibition? evidence from the antisaccade paradigm.

When it comes to measuring cognitive control and inhibition, the antisaccade paradigm is a popular task to apply. Usually, simple, perceptually and affectively neutral stimuli, e.g. white circles, are used. Recently, researchers also employed a version of the paradigm displaying emotional faces. Differences in cognitive processing due to stimulus size and emotional valence have not been investigated yet. Thus, in the present study, we applied both versions of the antisaccade paradigm in a healthy sample. In addition, we used scrambled faces to control for stimulus size and emotional valence. We hypothesised slower reaction times and higher error rates for emotional face stimuli compared to circular and scrambled ones as well as significant differences between individual emotions. In contrast to our hypotheses, results showed faster reaction times fewer errors for emotional faces compared to circular and scrambled stimuli. Furthermore, ANOVA models showed no meaningful differences between different emotions. Our study shows specific patterns in inhibitory control due to stimulus size and valence in an antisaccade eye-tracking task.

Effects of Alzheimer-Like Pathology on Homocysteine and Homocysteic Acid Levels-An Exploratory In Vivo Kinetic Study.

Hyperhomocysteinemia has been suggested potentially to contribute to a variety of pathologies, such as Alzheimer's disease (AD). While the impact of hyperhomocysteinemia on AD has been investigated extensively, there are scarce data on the effect of AD on hyperhomocysteinemia. The aim of this in vivo study was to investigate the kinetics of homocysteine (HCys) and homocysteic acid (HCA) and effects of AD-like pathology on the endogenous levels. The mice received a B-vitamin deficient diet for eight weeks, followed by the return to a balanced control diet for another eight weeks. Serum, urine, and brain tissues of AppNL-G-F knock-in and C57BL/6J wild type mice were analyzed for HCys and HCA using LC-MS/MS methods. Hyperhomocysteinemic levels were found in wild type and knock-in mice due to the consumption of the deficient diet for eight weeks, followed by a rapid normalization of the levels after the return to control chow. Hyperhomocysteinemic AppNL-G-F mice had significantly higher HCys in all matrices, but not HCA, compared to wild type control. Higher serum concentrations were associated with elevated levels in both the brain and in urine. Our findings confirm a significant impact of AD-like pathology on hyperhomocysteinemia in the AppNL-G-F mouse model. The immediate normalization of HCys and HCA after the supply of B-vitamins strengthens the idea of a B-vitamin intervention as a potentially preventive treatment option for HCys-related disorders such as AD.

Pyrrolic and Dipyrrolic Chlorophyll Degradation Products in Plants and Herbivores.

The degradation of chlorophyll, the omnipresent green pigment, has been investigated intensively over the last 30 years resulting in many elucidated tetrapyrrolic degradation products. With a comparison to the degradation of the structurally similar heme, we hereby propose a novel additional chlorophyll degradation mechanism to mono- and dipyrrolic products. This is the first proof of the occurrence of a family of mono- and dipyrrols in leaves that are previously only known as heme degradation products. This product family is also found in spit and feces of herbivores with specific metabolomic patterns reflecting the origin of the samples. Based on chromatographic and mass spectrometric evidence as well as on mechanistic considerations we also suggest several tentative new degradation products. One of them, dihydro BOX A, was fully confirmed as a novel natural product by synthesis and comparison of its spectroscopic data.

Total syntheses of the bilirubin oxidation end product Z-BOX C and its isomeric form Z-BOX D.

Oxidative degradation products of bilirubin (BOXes) are biologically highly active and certain BOXes cause long-lasting narrowing of cerebral blood vessels presumably with a significant role in subarachnoid hemorrhage. Due to the fact that mode of action as well as fate of these BOXes is widely unknown, larger amounts of these bilirubin degradation end products are required. The total synthesis of colorless (Z)-3-(5-(2-amino-2-oxoethylidene)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-3-yl)propanoic acid (BOX C) succeeds via a seven-step procedure with a total yield of 20%. Its isomeric form (Z)-3-(2-(2-amino-2-oxoethylidene)-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)propanoic acid (BOX D) can be prepared via a five-step protocol with a yield of 30%. NMR and crystallographic studies reveal that charge delocalization within the conjugated π-systems of BOXes C and D is negligible. Exposure of solutions of Z-BOX C and Z-BOX D to bright sunlight leads to Z/E-isomerization and mixtures of the respective E/Z-BOXes C and D.

In vivo and in vitro identification of Z-BOX C - a new bilirubin oxidation end product.

A new bilirubin oxidation end product (BOX) was isolated and characterized. The formation of the so-called Z-BOX C proceeds from bilirubin via propentdyopents as intermediates. This BOX was detected in pathological human bile samples using liquid chromatography/mass spectrometry and has potential relevance for liver dysfunction and cerebral vasospasms.

Ethylene glycol revisited: Molecular dynamics simulations and visualization of the liquid and its hydrogen-bond network.

Molecular dynamics simulations of liquid ethylene glycol described by the OPLS-AA force field were performed to gain insight into its hydrogen-bond structure. We use the population correlation function as a statistical measure for the hydrogen-bond lifetime. In an attempt to understand the complicated hydrogen-bonding, we developed new molecular visualization tools within the Vish Visualization shell and used it to visualize the life of each individual hydrogen-bond. With this tool hydrogen-bond formation and breaking as well as clustering and chain formation in hydrogen-bonded liquids can be observed directly. Liquid ethylene glycol at room temperature does not show significant clustering or chain building. The hydrogen-bonds break often due to the rotational and vibrational motions of the molecules leading to an H-bond half-life time of approximately 1.5 ps. However, most of the H-bonds are reformed again so that after 50 ps only 40% of these H-bonds are irreversibly broken due to diffusional motion. This hydrogen-bond half-life time due to diffusional motion is 80.3 ps. The work was preceded by a careful check of various OPLS-based force fields used in the literature. It was found that they lead to quite different angular and H-bond distributions.

Inhibition/activation in bipolar disorder: validation of the Multidimensional Assessment of Thymic States scale (MAThyS).

BACKGROUND: One of the major issues in clinical practice is the accurate differential diagnosis between mixed states and depression, often leading to inappropriate prescriptions of antidepressants in mixed states, and as a consequence, increasing the risk of manic switch and suicide. In order to better define the spectrum of mixed states, it may be useful to develop a dimensional approach. In this context, the MAThyS (Multidimensional Assessment of Thymic States) scale was built to assess activation/inhibition levels in all bipolar mood episodes, and to determine whether a clinical description in terms of activation/inhibition can help better define bipolar states with which both manic and depressive symptoms are associated. The aim of this paper is the validation of the MAThyS scale in 141 bipolar patients in acute states (manic, hypomanic, mixed, or depressive). METHODS: The validation of the MAThyS scale was the primary outcome of this 24-week, phase III, open-label, olanzapine single-arm clinical trial. Principal component, factorial analysis, and Cronbach's coefficient calculation (internal consistency) were performed. Concurrent validity (correlations with 17-item Hamilton Depression Rating Scale [HAMD-17], Hamilton Anxiety Rating Scale [HAMA], and Young Mania Rating Scale [YMRS]) and responsiveness to the clinical intervention were assessed (change in MAThyS scale and effect size) at 6 and 24 weeks. RESULTS: Scree plot of eigenvalues identified a 2-dimension structure ("activation/inhibition level" and "emotional component"). Psychometric properties were good: Cronbach's coefficient was >0.9. Concurrent validity was good with low correlation (-0.19) with the HAMA scale and a higher correlation at baseline with the YMRS (0.72) and HAMD-17(-0.43). As expected, the activation state was predominant in manic, hypomanic, and mixed states while inhibition was predominant in depressive states. MAThyS score improvement was observed (effect size: -0.3 at 6 and 24 weeks). CONCLUSIONS: The MAThyS demonstrated good psychometric properties. The MAThyS scale may help clinicians to better discriminate and follow bipolar episodes, especially the broad spectrum of mixed episodes.

Eye Tracking in Patients with Parkinson's Disease Treated with Nabilone-Results of a Phase II, Placebo-Controlled, Double-Blind, Parallel-Group Pilot Study.

The topic of the therapeutic use of cannabinoids in Parkinson's disease (PD) is broadly discussed and frequently comes up in the outpatient clinic. So far, there are only a few randomized clinical trials assessing the effects of cannabinoids in PD. We are able to demonstrate a reduction in non-motor symptom (NMS) burden after the administration of nabilone. As impairment of attention and working memory have been described earlier as possible side effects, we assess cognitive performance using saccadic paradigms measured by an eye tracker. We do not observe a significant difference in any of the saccadic paradigms between PD patients on placebo versus those treated with nabilone. We, therefore, conclude that top-down inhibitory control is not affected by the tetrahydrocannabinol analogue. Nabilone did not significantly worsen cognitive performance and appears to be safe to use in selected PD patients who suffer from disabling NMS.

Cognitive dysfunction 1 year after COVID-19: evidence from eye tracking.

Increasing evidence suggests persistent cognitive dysfunction after COVID-19. In this cross-sectional study, frontal lobe function was assessed 12 months after the acute phase of the disease, using tailored eye tracking assessments. Individuals who recovered from COVID-19 made significantly more errors in all eye tracking tasks compared to age/sex-matched healthy controls. Furthermore, patients who were treated as inpatients performed worse compared to outpatients and controls. Our results show impaired inhibitory cortical control in individuals who recovered from COVID-19. The association between disease severity and its sequelae may contribute to a better understanding of post-COVID-19 cognitive function.

Photoisomerization Neutralizes Vasoconstrictive Activity of a Heme Degradation Product.

Delayed cerebral ischemia (DCI) caused by cerebral vasospasm is the leading determinant of poor outcome and mortality in subarachnoid hemorrhage (SAH) patients, but current treatment options lack effective prevention and therapy. Two substance families of heme degradation products (HDPs), bilirubin oxidation end products (BOXes) and propentdyopents (PDPs), are elicitors of pathologic cerebral hypoperfusion after SAH. Z-configured HDPs can be photoconverted into the corresponding E-isomers. We hypothesize that photoconversion is a detoxification mechanism to prevent and treat DCI. We irradiated purified Z-BOXes and Z-PDPs with UV/Vis light and documented the Z-E photoconversion. E-BOX A slowly reisomerizes to the thermodynamically favored Z-configuration in protein-containing media. In contrast to vasoconstrictive Z-BOX A, E-BOX A does not cause vasoconstriction in cerebral arterioles in vitro and in vivo in wild-type mice. Our results enable a critical assessment of light-induced intrathecal photoconversion and suggest the use of phototherapy to prevent and cure HDP-mediated cerebral vasospasms.

Hydrogen Bonding and Dielectric Spectra of Ethylene Glycol-Water Mixtures from Molecular Dynamics Simulations.

Mixtures of ethylene glycol with water are a prominent example of media with variable viscosity. Classical molecular dynamics simulations at room temperature were performed for mixtures of ethylene glycol (EG) and water with EG mole fractions of xE = 0.0, 0.1, 0.2, 0.4, 0.6, 0.9, 1.0. The calculated dielectric loss spectra were in qualitative agreement with experiment. We found a slightly overestimated slowdown of the dynamics with increasing EG concentration compared to experimental data. Statistics of the hydrogen bond network and hydrogen bond lifetimes were derived from suitable time correlation functions and also show a slowdown in the dynamics with increasing xE. A similar picture is predicted for the time scales of EG conformer changes and for molecular reorientation. A slight blue shift was obtained for the power spectra of the molecular center of mass motion. The results were used to give a qualitative interpretation of the origin of three different relaxation times that appear in experimental complex dielectric spectra and of their change with xE.

Isolation and Identification of Intermediates of the Oxidative Bilirubin Degradation.

Four endogenous products of oxidative bilirubin degradation were isolated and fully characterized. The constitutional isomers belong to the propentdyopents (PDPs). Their structures and further oxidative transformations to biologically active bilirubin oxidation end products (Z-BOXes) are reported. Using liquid chromatography-mass spectrometry protocols, PDPs were detected in human bile and gallstones. Given the recent interest in BOXes as effectors in cerebral vasospasms and liver dysfunction, co-occurring PDPs represent an additional potentially active compound class to be considered.

Mean Deviation of Inter-rater Scoring (MDIS): a simple tool for introducing conformity into groups of clinical investigators.

In spite of considerable progress over the past decade, training investigators for inter-rater reliability for clinical trials remains a major problem. The aim of the present study was to promote a new tool to increase data homogeneity by introducing conformity into groups of clinical investigators. The investigators scoring grid we are proposing-the Mean Deviation of Inter-rater Scoring (MDIS)-involves the calculation of the score deviation for each investigator relative to the median score of an expert group who had evaluated the same videotape-recorded clinical case. Whatever the scale, the score deviation is calculated as the absolute deviation value from the median score obtained by the experts for each item. The MDIS value is then evaluated from all the scores given by an investigator by dividing the total sum of the previously defined values by the number of items of the scale. Some examples from practice are given using several rating scales: (i) Hamilton Anxiety Rating Scale; (ii) Hamilton Depression Rating Scale; (iii) Montgomery Asberg Depression Rating Scale; and (iv) Positive And Negative Symptoms Scale. Finally, such a method could also be employed by experts to evaluate the quality of videotape-recorded clinical cases used in clinical trials, as well as by teachers to evaluate initial or continuous medical training.

Vacancy patterning and patterning vacancies: controlled self-assembly of fullerenes on metal surfaces.

A density functional theory study accounting for van der Waals interactions reveals the potential of metal surface vacancies as anchor points for the construction of user-defined 2D patterns of adsorbate molecules via a controlled self-assembly process. Vice versa, energetic criteria indicate the formation of regular adsorbate-induced vacancies after adsorbate self-assembly on clean surfaces. These processes are exemplified by adsorbing C60 fullerene on Al(111), Au(111), and Be(0001) surfaces with and without single, triple, and septuple atom pits. An analysis of vacancy-adatom formation energetics precedes the study of the adsorption processes.