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Abstract Background Working memory (WM) impairment is a common phenomenon after stroke; however, its management in rehabilitation is less researched. This systematic review and meta-analysis aimed to provide a quantitative synthesis of the impact of computerised cognitive training (CCT) and transcranial direct current stimulation (tDCS) on WM span in post-stroke individuals. Methods The literature search in PubMed, Embase, Scopus, and Cochrane Library focused on randomized controlled trials testing the effect of CCT and tDCS on treated stroke patients as compared to untreated controls. Neuropsychological instruments such as Digit Span Forward/Backward and Visual Span Forward Tests defined the outcome of WM span. After extracting study characteristics and quality assessment using the Cochrane Risk of Bias Tool, we conducted a meta-analysis and meta-regression using standardised mean differences. Results The search yielded 4142 articles, nine of which (N = 461) fulfilled the inclusion criteria. In the case of CCT, we found significant improvement in Digit Span Backward Test (Z = 2.65, P = 0.008; 95% CI [0.10, 0.67]) and Visual Span Forward Test performance (Z = 3.05, P = 0.002; 95% CI [0.15, 0.69]), while for tDCS, we could not find a sufficient number of studies for the analysis. Furthermore, no significant moderating factor was found in the meta-regression. Conclusions In conclusion, CCT appears to be a suitable choice to enhance WM span performance after stroke. However, further research is needed to investigate the effect of tDCS due to the limited number of studies. Trial registration The meta-analysis was conducted according to PRISMA (Preferred Reporting of Systematic Reviews and Meta-Analyses) standards with a PROSPERO registration protocol (ID: CRD42023387182).

Abstract Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.

Introduction: Natalizumab (NAT), a highly effective disease modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS), was approved for clinical use in Hungary on February 1, 2010. In this study we aimed to assess its effectiveness in view of the concept of “No Evidence of Disease Activity” (NEDA-3), furthermore evaluate its effect on limb function, pathopsychological symptoms (cognition, fatigue, depression) and quality of life (QoL). Patients and methods: From February 1, 2010, to December 1, 2022, 121 eligible patients were consecutively enrolled from the MS center of the University of Szeged, Hungary. Here, we report data on 6-years of follow-up. First, we evaluated the proportion of patients reaching the NEDA-3 state and any possible influencing factors. Then, we assessed the change of upper and lower limb functions via the 9-hole-peg test (9HPT) and the 25-feet walk test (TW25F). Finally, we assessed the change of pathopsychological symptoms (cognition, fatigue, depression) and QoL via the BICAMS, FIS, BDI-II and MSQoL-54 questionnaires, and the possible influencing factors behind it. Results: Cumulatively, 97 patients (80.2 %) achieved NEDA-3 throughout the follow-up period. On a year-by-year basis, the proportion changed from 95.9 % in the 1st year to 84.3 %, 81.3 %, 76.4 %, 74.5 % and 78.9 % in the 2nd, 3rd, 4th, 5th and 6th year respectively (p

Abstract Purpose The present study tested the hypothesis that repeated anti-VEGF injections are associated with reduced retinal nerve fiber layer (RNFL) and minimum rim width (MRW) of the optic nerve head. Patients and methods Sixty-six patients with a history of intravitreal injections due to neovascular age-related macular degeneration were included. RNFL and MRW were measured using optical coherence tomography (Spectralis OCT, Heidelberg Engineering, Heidelberg, Germany). Results Mean global RNFL was 90.62 μm and both RNFL as well as MRW significantly decreased with advanced age (p = 0.005 and p = 0.019, respectively). Correlating for the number of injections, no significant impact on RNFL was found globally (p = 0.642) or in any of the sectors. In contrast, however, global MRW was significantly reduced with increasing numbers of intravitreal injections (p = 0.012). The same holds true when adjusted for the confounding factor age (RNFL p = 0.566 and MRW p = 0.023). Conclusion Our study shows that repeated intravitreal injections due to choroidal neovascularization seem to have a deleterious effect on MRW but not on RNFL. This suggests that MRW is a more sensitive marker than RNFL for evaluating the effect of frequent intravitreal injections on the optic nerve head since it seems to be the first structure affected.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the death of motor neurons, the aetiology of which is essentially unknown. Here, we present an integrative epigenomic study in blood samples from seven clinically characterised sporadic ALS patients to elucidate molecular factors associated with the disease. We used clinical exome sequencing (CES) to study DNA variants, DNA-RNA hybrid immunoprecipitation sequencing (DRIP-seq) to assess R-loop distribution, and reduced representation bisulfite sequencing (RRBS) to examine DNA methylation changes. The above datasets were combined to create a comprehensive repository of genetic and epigenetic changes associated with the ALS cases studied. This repository is well-suited to unveil new correlations within individual patients and across the entire patient cohort. The molecular attributes described here are expected to guide further mechanistic studies on ALS, shedding light on the underlying genetic causes and facilitating the development of new epigenetic therapies to combat this life-threatening disease.

Fatigue is one of the most frequent complaints of patients with multiple sclerosis (MS). The Fatigue Impact Scale (FIS), one of the 30 available fatigue questionnaires, is commonly applied because it evaluates multidimensional aspects of fatigue. The chief objectives of this study were to validate FIS and evaluate the psychometric properties of MS patients in Serbia. One hundred and twenty-one (121) MS patients and one hundred and twenty-two (122) age-, gender- and education-matched healthy control (HC) subjects completed the FIS and the Beck Depression Inventory. Internal consistency of the FIS subscales was determined using Cronbach’s Alpha Coefficient. Test/retest reliability with an intra-class correlation coefficient (ICC) for each FIS subscale was performed. The total FIS score and subscale scores showed statistically significant differences between the MS patients and the HC subjects in both FIS sessions. Cronbach’s Alpha was 0.966. All ICCs were statistically significant (p < 0.05). The Serbian version of this instrument may be useful as a clinical measure for fatigue and functionality in patients with MS.

Abstract We previously showed the anti-inflammatory effects of kynurenic acid (KYNA) and its brain-penetrable analog N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide (SZR104) both in vivo and in vitro. Here, we identified the cytomorphological effects of KYNA and SZR104 in secondary microglial cultures established from newborn rat forebrains. We quantitatively analyzed selected morphological aspects of microglia in control (unchallenged), lipopolysaccharide (LPS)-treated (challenged), KYNA- or SZR104-treated, and LPS + KYNA or LPS + SZR104-treated cultures. Multicolor immunofluorescence labeling followed by morphometric analysis (area, perimeter, transformation index, lacunarity, density, span ratio, maximum span across the convex hull, hull circularity, hull area, hull perimeter, max/min radii, mean radius, diameter of bounding circle, fractal dimension, roughness, circularity) on binary (digital) silhouettes of the microglia revealed their morphological plasticity under experimental conditions. SZR104 and, to a lesser degree, KYNA inhibited proinflammatory phenotypic changes. For example, SZR104 treatment resulted in hypertrophied microglia characterized by a swollen cell body, enlarged perimeter, increased transformation index/decreased circularity, increased convex hull values (area, perimeter, mean radius, maximum span, diameter of the bounding circle and hull circularity), altered box-counting parameters (such as fractal dimension), and increased roughness/decreased density. Taken together, analysis of cytomorphological features could contribute to the characterization of the anti-inflammatory activity of SZR104 on cultured microglia.

Abstract Background The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements. Findings Significantly decreased L-kynurenine (KYN, p

Migraine is a debilitating neurological disorder characterized by recurring episodes of throbbing headaches that are frequently accompanied by sensory disturbances, nausea, and sensitivity to light and sound [...]

Welcome to Biomedicines’ 10th Anniversary Special Issue, a journey through the human mind’s labyrinth and complex neurological pathways [...]

Translational research in neurological and psychiatric diseases is a rapidly advancing field that promises to redefine our approach to these complex conditions [...]

On a Wendelstein 7-X (W7-X), an alkali metal beam (AMB) diagnostic system was installed in order to measure the plasma edge electron density profiles and turbulence transport. A sodium beam was injected in the plasma, and the light emission was observed by an optical system. During the last operation phase, OP1.2b campaign trial spectral measurements were performed with a dedicated optical branch. The results showed the emergence of potential CX lines in the light spectra during sodium injection. The lines were identified as Carbon III, which were the dominant lines observed by other diagnostics at the edge plasma. Based on these results, an additional dedicated optical system was developed and installed in 2021 for the upcoming operational phase, OP2. The optics were designed for multiple purposes: spectral measurements for the AMB system and for a He/Ne gas jet. The system was designed to allow implementation of further diagnostics on this port later (e.g., coherence imaging system). The details of the implementation of the design requirements and the main challenges of the manufacturing process and installation are discussed in this paper.

Neurodegeneration poses a significant challenge for the fields of neuroscience and medicine, as it is the underlying cause of the development and advancement of numerous neurodegenerative and psychiatric disorders [...]

Neuroscience, neurology, and psychiatry are rapidly evolving fields that aim to understand the complex mechanisms underlying brain function and dysfunction, as well as to develop effective interventions for various neurological and psychiatric disorders [...]

The orexin/hypocretin neuropeptide family has emerged as a focal point of neuroscientific research following the discovery that this family plays a crucial role in a variety of physiological and behavioral processes. These neuropeptides serve as powerful neuromodulators, intricately shaping autonomic, endocrine, and behavioral responses across species. Notably, they serve as master regulators of vigilance and stress responses; however, their roles in food intake, metabolism, and thermoregulation appear complementary and warrant further investigation. This narrative review provides a journey through the evolution of our understanding of the orexin system, from its initial discovery to the promising progress made in developing orexin derivatives. It goes beyond conventional boundaries, striving to synthesize the multifaceted activities of orexins. Special emphasis is placed on domains such as stress response, fear, anxiety, and learning, in which the authors have contributed to the literature with original publications. This paper also overviews the advancement of orexin pharmacology, which has already yielded some promising successes, particularly in the treatment of sleep disorders.

A support laboratory has been set up to study pellet production, launch and shattering of cryogenic protium, deuterium, and neon pellets for the ITER disruption mitigation system, which plans to use 28.5 × 57 mm (diameter × length) protium, neon an mixture pellets in the Shattered Pellet Injectors. Such large protium pellets have not been produced and launched before, therefore the desublimation and launch process have been studied in detail in two steps. First 19 mm diameter pellets were produced, followed by the demonstration of the final pellet size. Pellet desublimation recipes were established for all pellet types, and it was found that, under certain conditions, even the large neon pellets can be launched with a propellant gas pulse, without requiring a mechanical punch device. This is attributed to cryogenic snow formation on the surface of the pellet. Conditions for the snow formation are studied and tendencies are understood using simple calculations.

Abstract Background Migraine is a primary headache with genetic susceptibility, but the pathophysiological mechanisms are poorly understood, and it remains an unmet medical need. Earlier we demonstrated significant differences in the transcriptome of migraineurs' PBMCs (peripheral blood mononuclear cells), suggesting the role of neuroinflammation and mitochondrial dysfunctions. Post-transcriptional gene expression is regulated by miRNA (microRNA), a group of short non-coding RNAs that are emerging biomarkers, drug targets, or drugs. MiRNAs are emerging biomarkers and therapeutics; however, little is known about the miRNA transcriptome in migraine, and a systematic comparative analysis has not been performed so far in migraine patients. Methods We determined miRNA expression of migraineurs’ PBMC during (ictal) and between (interictal) headaches compared to age- and sex-matched healthy volunteers. Small RNA sequencing was performed from the PBMC, and mRNA targets of miRNAs were predicted using a network theoretical approach by miRNAtarget.com™. Predicted miRNA targets were investigated by Gene Ontology enrichment analysis and validated by comparing network metrics to differentially expressed mRNA data. Results In the interictal PBMC samples 31 miRNAs were differentially expressed (DE) in comparison to healthy controls, including hsa-miR-5189-3p, hsa-miR-96-5p, hsa-miR-3613-5p, hsa-miR-99a-3p, hsa-miR-542-3p. During headache attacks, the top DE miRNAs as compared to the self-control samples in the interictal phase were hsa-miR-3202, hsa-miR-7855-5p, hsa-miR-6770-3p, hsa-miR-1538, and hsa-miR-409-5p. MiRNA-mRNA target prediction and pathway analysis indicated several mRNAs related to immune and inflammatory responses (toll-like receptor and cytokine receptor signalling), neuroinflammation and oxidative stress, also confirmed by mRNA transcriptomics. Conclusions We provide here the first evidence for disease- and headache-specific miRNA signatures in the PBMC of migraineurs, which might help to identify novel targets for both prophylaxis and attack therapy.

Abstract Background Wilson’s disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). The co-occurrence of these two, although not unheard of in literature, is still considered to be very rare and can give rise to diagnostic difficulties. Also, comorbidity in MS highly influences quality of life and disease progression, which makes the timely diagnosis and treatment of these conditions essential. Case presentation The aim of this study is to present a patient exhibiting symptoms of both MS and Wilson’s disease, as well as to conduct a detailed review of previously reported cases. The patient’s neurological symptoms (sensory disorder) as well as MRI and CSF findings were characteristic for MS. The diagnosis of MS preceded that of Wilson’s disease and was relatively mild in course. Currently, the patient receives cladribine as an immunomodulatory treatment after escalation from glatiramer acetate therapy. Apart from one episode of acute hepatic decompensation, during which transfusion, albumin supplementation and diuretic treatment was necessary, Wilson’s disease manifested as chronic impairment of liver function. The diagnosis of Wilson’s disease was established by the analysis of serum coeruloplasmin levels, histological examination and genetic findings. Continuous oral penicillamine therapy led to the slow normalization of hepatic function and significant amelioration of the patient’s symptoms. Correlating with cases previously reported, the course of MS was relatively mild, and like in three out of four other known cases, the symptoms of Wilson’s disease were mostly restricted to hepatic dysfunction. Conclusion The case presented in our report is similar to those reported before. The co-occurrence of the two diseases seems to be more a coincidence than a sharing of common factors in their pathogenesis; however, they are considered to influence one another. Regarding rare co-occurrences such as this one, every new case is of high importance, as it enables a better evaluation and understanding of the clinical presentations that are more characteristic of these cases, thus aiding the estimation of disease course as well as possible therapeutic choices.

Abstract Background During the first wave of the coronavirus disease 2019 (COVID-19) pandemic in 2020 outpatient care of neovascular age-related macular degeneration (nAMD) patients was severely reduced due to lockdown. Missed visits are known to be detrimental to patients in need of continued anti-vascular endothelial growth factor (VEGF) intravitreal injections (IVIs). The purpose of the study was to assess the effect of a month-long pause of regular visits and anti-VEGF IVIs in nAMD patients. Methods A retrospective study was performed. Patients were treated in a pro re nata (“as needed”) scheme. Distance (logMAR) and near (logRAD) visual acuity (VA), optical coherence tomography, delay between planned and actual visit date and the indication for IVI were assessed for 3 continous visits in the 6 months before lockdown (V-3, -2, -1) and the 2 visits after lockdown (V0, V + 1). For analysis of long-term impact, records for visits 1 years before and after lockdown (V-3, V + 2) were gathered. Results We included 166 patients (120 female, 46 male) with a median (range) age of 80.88 (59.8–99.36) years. Compared to V-1, distance VA was significantly worse at both V0 (0.27 ± 0.21 vs 0.31 ± 0.23 logMAR, p 0.05). Conclusions In nAMD patients whose visits and treatment were paused for a month during the first wave of the COVID-19 pandemic, we found a loss of VA immediately after lockdown, which persisted during follow-up despite re-established anti-VEGF treatment. In the short term, length of delay was predictive for loss of reading VA. The comparison of development of VA during the year before and after the lockdown showed a progression of nAMD related VA loss which may have been accelerated by the disruption of regular visits and treatment. Trial registration This article does not report the outcome of a health care intervention. This retrospective study was therefore not registered in a clinical trials database.