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This article presents demographic, socio-economic and detailed adherence to medication data from 429 patients with neurological disorders. Adherence to medication was assessed using the German Stendal Adherence to Medication Score (SAMS). The SAMS questionnaire includes 18 questions forming a cumulative scale (0 - 72) in which 0 indicates complete adherence and 72 complete non-adherence. The SAMS covers different aspects of adherence/non-adherence, such as intentional modification of medication, missing knowledge about reasons/dosage/timing of medication and forgetting to take medication. The dataset allows determining different reasons and clusters of adherence to medication. The dataset can be used as by clinicians, pharmacists and academia for further research and as reference. The dataset can also be used in a large range of other topics where demographic and socio-economic parameters are relevant. The data presented herein is associated with the research article "Clusters of non-adherence to medication in neurological patients" [1] and available on Mendeley https://data.mendeley.com/datasets/ny2krr3vgg/1.

Parkinson's disease is a common multisystem neurodegenerative disorder characterized by typical motor and non-motor symptoms. There is an urgent need for biomarkers for assessment of disease severity, complications and prognosis. In addition, biomarkers reporting the underlying pathophysiology assist in understanding the disease and developing neuroprotective therapies. Ultimately, biomarkers could be used to develop a more efficient personalized approach for clinical trials and treatment strategies. With the goal to improve quality of life in Parkinson's disease it is essential to understand and objectively monitor non-motor symptoms. This narrative review provides an overview of recent developments of biomarkers (biofluid samples and imaging) for three common neuropsychological syndromes in Parkinson's disease: dementia, fatigue, and depression.

Amyotrophic lateral sclerosis is characterized by progressive death of motor neurons (MNs) with glutamate excitotoxicity and mitochondrial Ca 2+ overload as critical mechanisms in disease pathophysiology. We used MNs from G93A hSOD1 and nontransgenic embryonic cultures and adult mice to analyze the expression of the main mitochondrial calcium uniporter (MCU). MCU was overexpressed in cultured embryonic G93A hSOD1 MNs compared to nontransgenic MNs but downregulated in MNs from adult G93A hSOD1 mice. Furthermore, cultured embryonic G93A hSOD1 were rescued from kainate-induced excitotoxicity by the Ca 2+ /calmodulin-dependent protein kinase type II inhibitor; KN-62, which reduced MCU expression in G93A hSOD1 MNs. MCU activation via kaempferol neither altered MCU expression nor influenced MN survival. However, its acute application served as a fine tool to study spontaneous Ca 2+ activity in cultured neurons which was significantly altered by the mutated hSOD1. Pharmacological manipulation of MCU expression might open new possibilities to fight excitotoxic damage in amyotrophic lateral sclerosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Stroke robustly stimulates adult neurogenesis in the hippocampal dentate gyrus. It is currently unknown whether this process induces beneficial or maladaptive effects, but morphological and behavioral studies have reported aberrant neurogenesis and impaired hippocampal-dependent memory following stroke. However, the intrinsic function and network incorporation of adult-born granule cells (ABGCs) after ischemia is unclear. Using patch-clamp electrophysiology, we evaluated doublecortin-positive (DCX + ) ABGCs as well as DCX - dentate gyrus granule cells 2 weeks after a stroke or sham operation in DCX / DsRed transgenic mice of either sex. The developmental status, intrinsic excitability, and synaptic excitability of ABGCs were accelerated following stroke, while dendritic morphology was not aberrant. Regression analysis revealed uncoupled development of intrinsic and network excitability, resulting in young, intrinsically hyperexcitable ABGCs receiving disproportionately large glutamatergic inputs. This aberrant functional maturation in the subgroup of ABGCs in the hippocampus may contribute to defective hippocampal function and increased seizure susceptibility following stroke. SIGNIFICANCE STATEMENT Stroke increases hippocampal neurogenesis but the functional consequences of the postlesional response is mostly unclear. Our findings provide novel evidence of aberrant functional maturation of newly generated neurons following stroke. We demonstrate that stroke not only causes an accelerated maturation of the intrinsic and synaptic parameters of doublecortin-positive, new granule cells in the hippocampus, but that this accelerated development does not follow physiological dynamics due to uncoupled intrinsic and synaptic maturation. Hyperexcitable immature neurons may contribute to disrupted network integration following stroke., (Copyright © 2019 the authors 0270-6474/19/391755-12$15.00/0.)

Objectives: To determine the impact of disease progression on health-related quality of life in amyotrophic lateral sclerosis (ALS)., Methods: A total of 161 patients with ALS were enrolled. Assessments included the revised ALS Functional Rating Scale and the ALS Assessment Questionnaire (ALSAQ-40). Data analysis comprised linear regression and multivariate analyses., Results: ALSFRS-R score (β = 0.75, p < 0.001), depression (β = 0.08, p < 0.001), pain (β = 0.07, p < 0.001), hopelessness (β = 0.07, p = 0.001), and progression rate (β = 0.02, p = 0.02) explained 76% of the ALSAQ-40 summary index variance. Progression rate alone explained 7% of the ALSAQ-40 summary index variance. The subdomains of emotional well-being, followed by ADL, and finally communication and eating were most strongly influenced by progression rate., Conclusion: Our study demonstrates the importance of physical health for emotional well-being. In particular, slower disease progression is associated with higher levels of emotional well-being in ALS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Microglia, the key innate immune cells in the brain, have been reported to drive brain aging and neurodegenerative disorders; however, few studies have analyzed microglial senescence and the impact of aging on the properties of microglia. In the present study, we characterized senescence- and aging-associated phenotypes of murine brain microglia using well-accepted markers, including telomere length, telomerase activity, expression of p16 INK4a , p21, p53, senescence-associated β-galactosidase, and a senescence-associated secretory phenotype. Quantitative real-time polymerase chain reaction analysis and a Telomeric Repeat Amplification Protocol assay indicated shortened telomeres and increased telomerase activity in senescent microglia, whereas telomeres remained unaltered and telomerase activity was reduced in aged microglia. Senescent microglia upregulated p16 INK4a , p21, and p53, whereas acutely isolated microglia from the aged brain only exhibited a modest upregulation of p16 INK4a . Senescent microglia showed decreased proliferation, while it was unchanged in aged microglia. Furthermore, microglia at late passages strongly upregulated expression of the senescent marker senescence-associated β-galactosidase. Senescent and aged microglia exhibited differential activation profiles and altered responses to stimulation. We conclude that microglia from the aged mouse brain do not show typical senescent changes because their phenotype and functional response strongly differ from those of senescent microglia in vitro., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sensorimotor adaptation is driven by mismatch errors between desired movements and actual movement outcomes. A mismatch error can be minimized by adjusting movements or by altering the interpretation of sensory information. While the effect of mismatch errors on the motor system has received much attention, the contribution of somatosensory feedback, particularly the sensory-motor interplay in the process of adaptation, remains poorly understood. Our study analyzes the impact of peripheral deefferentation on the plasticity of the brain networks responsible for sensory-motor adaptation, focusing particularly on changes in the processing of somatosensory information. For this aim, task-based and resting-state functional MRI was performed on 24 patients in the acute state of a left-sided idiopathic peripheral facial nerve palsy. The functional connectivity of cortical and subcortical networks was analyzed and compared to a healthy control group. We found a strong involvement of the somatosensory system and the thalamus in the adaptation process following an acute peripheral deefferentation. The investigated network shows the principal pattern of a reduced connectivity between cortical areas, while the connectivity to subcortical areas (the basal ganglia and the thalamus) is increased. We suggest that the increased connectivity between the subcortical and cortical structures indicates an active sensory-motor adaptation process. We further hypothesize that the decreased functional connectivity at the cortical level reflects an unsuccessful sensorimotor adaptation process due to the inability to solve the somatosensory-motor mismatch. These results extend our understanding of the somatosensory-motor interaction in response to a mismatch signal and highlight the importance of the thalamus in this process., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a multisystemic neurodegenerative disorder. Given that peripheral blood mononuclear cells (PBMCs) serve as a "window to the central nervous system" we aimed to answer whether endoplasmic reticulum (ER) stress in ALS-PBMCs is related to disease aggressiveness. We studied ER stress in the PBMCs of 49 patients with ALS and 31 age- and sex-matched healthy controls. The expression of a main ER stress marker, activating transcription factor 6 (ATF6), was significantly higher in ALS compared to controls, but did not correlate with age, disease severity, disease duration and disease progression rate. When ATF6 expression levels were plotted against relative D50 (rD50)-derived disease phases derived from the D50 ALS model, two distinct clusters of patients were observed: cluster 1, with progressively increasing ATF6 expression levels and cluster 2, which demonstrated stable ATF6 expression over the disease course. Individuals in the two clusters did not significantly differ in terms of ALS Functional Rating Scale-Revised (ALSFRS-R), disease aggressiveness, disease duration and subtype. However, patients with the increasing ATF6 level were significantly younger, indicating that aging processes might be related to ER stress in ALS. Our data suggest that the reaction to ER stress during disease course may be compromised in older patients with ALS.

Background: Idiopathic cervical dystonia (CD) is a chronic movement disorder characterized by impressive clinical symptoms and the lack of clear pathological findings in clinical diagnostics and imaging. At present, the injection of botulinum toxin (BNT) in dystonic muscles is an effective therapy to control motor symptoms and pain in CD., Objectives: We hypothesized that, although it is locally injected to dystonic muscles, BNT application leads to changes in brain and network activity towards normal brain function., Methods: Using 3 T functional MR imaging along with advanced analysis techniques (functional connectivity, Granger causality, and regional homogeneity), we aimed to characterize brain activity in CD (17 CD patients vs. 17 controls) and to uncover the effects of BNT treatment (at 6 months)., Results: In CD, we observed an increased information flow within the basal ganglia, the thalamus, and the sensorimotor cortex. In parallel, some of these structures became less responsive to regulating inputs. Furthermore, our results suggested an altered somatosensory integration. Following BNT administration, we noted a shift towards normal brain function in the CD patients, especially within the motor cortex, the somatosensory cortex, and the basal ganglia., Conclusion: The changes in brain function and network activity in CD can be interpreted as related to the underlying cause, the effort to compensate or a mixture of both. Although BNT is applied in the last stage of the cortico-neuromuscular pathway, brain patterns are shifted towards those of healthy controls., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Motor neurons are markedly vulnerable to excitotoxicity mostly by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) stimulation and are principal targets in the neurodegenerative disease Amyotrophic Lateral Sclerosis. Interferon-gamma (IFN-γ), a pro-inflammatory cytokine, can independently cause neuronal dysfunction by triggering calcium influx through a calcium-permeable complex of IFN-γ receptor 1(IFNGR1) subunit and AMPAR subunit GluR1. This receptor complex is formed via a non-canonical neuron-specific IFN-γ pathway that involves Jak1/Stat1 and Protein Kinase A. In this study, we explore the expression of the pathway's participants for the first time in the hSOD1G93A Amyotrophic Lateral Sclerosis mouse model. Elevated IFNGR1 and GluR1 are detected in motor neurons of hSOD1G93A symptomatic mice ex vivo, unlike the downstream targets - Jak1, Stat1, and Protein Kinase A. We, also, determine effects of IFN-γ alone or in the presence of an excitotoxic agent, kainate, on motor neuron survival in vitro. IFN-γ induces neuronal damage, but does not influence kainate-mediated excitotoxicity. Increased IFNGR1 can most likely sensitize motor neurons to excitotoxic insults involving GluR1 and/or pathways mediated by IFN-γ, thus, serving as a potential direct link between neurodegeneration and inflammation in Amyotrophic Lateral Sclerosis., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out., Objective: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors., Method: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage., Results: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed., Conclusion: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment.

Ischemic stroke due to an acute occlusion of the extracranial internal carotid artery (eICA) is associated with high morbidity and mortality. The best treatment option remains unclear. This study aims to increase the available therapeutic experience documented for surgical recanalization of acute eICA occlusions. We retrospectively reviewed all hospital records of the University Hospital Jena between 2006 and 2018 to identified patients with acute ischemic stroke due to an occlusion of the eICA who underwent emergent surgical recanalization. We analyzed clinical data, surgical reports, imaging data, and outpatient records. The primary outcome parameter was the modified Rankin Scale (mRS) at 3 months. During the survey, 12 patients (mean age: 62.3 ± 10.8 years; range: 35-87) underwent emergent surgical recanalization for an acutely symptomatic eICA occlusion. All patients presented with neurological deficits with a mean National Institutes of Health Stroke Scale score at admission of 15.0 ± 5.1 (range 2-23). Patients were selected for surgery mainly due to the extent of the perfusion mismatch, while stroke severity and age were also considered. The median time from symptom onset to surgery was 309 ± 122 minutes (range 112-650 minutes). Complete recanalization was obtained in all 12 patients. No patient deteriorated postoperatively, no intracranial hemorrhage was observed, and no patient died in the following 3 months. Favorable outcomes (mRS: 0-2) after 3 months were achieved in 7 of 12 patients. The current study adds support to previous findings that the surgical recanalization of acute eICA occlusions is a possible and safe treatment option. However, a critical patient selection based on mismatch size in perfusion imaging is crucially important for successful treatment.

Neuroimaging in Amyotrophic Lateral Sclerosis (ALS) has steadily evolved from an academic exercise to a powerful clinical tool for detecting and following pathological change. Nevertheless, significant challenges need to be addressed for the translation of neuroimaging as a robust outcome-metric and biomarker in quality-of-care assessments and pharmaceutical trials. Studies have been limited by small sample sizes, poor replication, incomplete patient characterization, and substantial differences in data collection and processing. This has been further exacerbated by the substantial heterogeneity associated with ALS. Multi-center transnational collaborations are needed to address these methodological limitations and achieve representation of rare phenotypes. This review will use the example of the Neuroimaging Society in ALS (NiSALS) to discuss the set-up of a multi-center data sharing ecosystem and the flow of information between various stakeholders. NiSALS' founding objective was to establish best practices for the acquisition and processing of MRI data and establish a structure that allows continuous data sharing and therefore augments the ability to fully describe patients. The practical challenges associated with such a system, including quality control, legal, ethical, and logistical constraints, will be discussed, as will be recommendations for future collaborative endeavors. We posit that "global cohorts" of well-characterized sub-populations within the disease spectrum are needed to fully understand the complex interplay between neuroimaging and other clinical metrics used to study ALS.

In ovo studies are a valuable option in preclinical research, but imaging studies are severely limited by the costs of dedicated equipment needed for small-sized eggs. We sought to verify the feasibility of using larger, ostrich, eggs ( Struthio camelus ) for imaging on the PET/CT scanners used for routine clinical investigations. Methods: Ostrich eggs were incubated until shortly before hatching, prepared for intravitelline venous injection of contrast medium or radiotracer, and imaged using native CT, contrast-enhanced CT, and PET/CT. Any technical adaptations that were needed to improve the outcome were noted. Results: Of the 34 eggs initially incubated, 12 became fully available for imaging of embryonal development. In ovo imaging with conventional PET/CT not only was feasible but also provided images of good quality, including on dynamic PET imaging. Conclusion: In ovo imaging with ostrich eggs and routine clinical scanners may allow broader application of this field of preclinical research, obviating costly dedicated equipment and reducing the number of animals needed for classic animal research. Further experiments are warranted to refine this novel approach, especially to reduce motion artifacts and improve monitoring of viability., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-κB, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-κB, but rather as a failure to induce or relocate telomerase.

Aims High concentrations of air pollutants are associated with increased risk for myocardial infarction. The European Union has defined statutory limits for air pollutants based on upper absolute concentrations. We evaluated the association between rapid changes in air pollutants and the risk of myocardial infarction independently of absolute concentrations. Methods and results Using a hospital-based case-crossover study, effects of 24h changes of nitrogen oxides (NO X/2 ), particulate matter (PM 10 ), and ozone on the risk of myocardial infarction was assessed in 693 patients. In the overall population, increases of NO X of more than 20 µg/m 3 within 24 h were associated with an increase in the risk of myocardial infarction by up to 121% (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.19-4.08). Comparably, rapid increases of NO 2 of more than 8 µg/m 3 tended to increase myocardial infarction risk by 73% (OR 1.73, 95% CI 0.91-3.28) while myocardial infarction risk decreased by 60% after a decrease of NO 2 concentration of more than 8 µg/m 3 (OR 0.4, 95% CI 0.21-0.77), suggesting a close-to-linear association. While results for ozone concentrations were ambiguous, rapid change in PM 10 was not associated with myocardial infarction risk. Conclusion Dynamics and extent of increase in nitrogen oxide concentrations may be an independent risk factor for myocardial infarction. As there are currently no European Union statutory limits reflecting this dynamic variation of air pollutants on a daily basis, the results urgently call for confirming studies in different geographical regions to verify the observations.

Objective: Many patients with dizziness and vertigo are of older age. It is still unclear which age-associated factors play a role in the treatment of dizziness and vertigo. Therefore, age-associated characteristics of patients subjected to an interdisciplinary day care approach for chronic vertigo and dizziness were analyzed. Subjects and Methods: 650 patients with chronic dizziness/vertigo subjected to a multimodal vestibular rehabilitation day care program were analyzed. Information concerning age, gender, medical diagnosis, medical consultations, technical diagnostics performed and therapy achieved before attending the clinic were collected. Furthermore, data were gathered using the Vertigo Severity Scale (VSS), Hospital Anxiety and Depression Scale (HADS), Mobility Inventory (MI), as well as the intensity of and the distress due to vertigo/dizziness using visual analog scales. As a follow-up, the VSS, HADS, MI, and the visual analog scales were collected again 6 months after attending the therapy program. Three age groups were compared to each other (<41, 41-65, and >65 years of age). Results: One-third of the patients were older than 65 years. This group had typical diagnoses with mainly organic deficits. In contrast to the dominance of mainly multifactorial, organic deficits the older patients reported less medical consultations, fewer technical diagnostics and even fewer treatments than the younger patients. The elderly scored significantly lower in total VSS, in VSS-V (vestibular-balance subscale), in VSS-A (autonomic-anxiety subscale) and in HADS-anxiety. Psychological diagnoses were clearly associated to the younger patients. 424 patients (65.2%) completed the follow-up questionnaire 6 months after attending the therapy week. The older patients revealed improvements of VSS-V and the Avoidance Alone scale of MI as well as decreased distress due to vertigo/dizziness. Conclusion: In the older patients, who took part in our vestibular rehabilitation program, mainly somatic deficits prevail while anxiety plays a minor role compared to young and middle aged patients. Older patients profited from vestibular rehabilitation especially in mobility and vestibular-balance. Therefore, vestibular rehabilitation programs for the elderly with a focus on physio- and occupational therapeutic interventions and less cognitive behavioral therapy may be reasonable.

Objective: To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE)., Methods: This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge., Results: Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI., Conclusion: In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.

A common cognitive problem reported by older people is compromised face recognition, which is often paralleled by age-related changes in face-sensitive and memory-related components in event-related brain potentials (ERPs). We developed a new training using photorealistic caricatures based on evidence that caricatures are beneficial for people with compromised face processing. Twenty-four older participants (62-75 yrs, 13 female) completed 12 training sessions (3 per week, 60 min each) and 24 older participants (61-76 yrs, 12 female) acted as controls. Before and after training (or waiting), participants took part in a diagnostic test battery for face processing abilities, and in ERP experiments on face learning and recognition. Although performance improvements during the training provided little evidence for generalization to other face processing tasks, ERPs showed substantial training-related enhancements of face-sensitive ERPs. Specifically, we observed marked increases of the N170, P200 and N250 components, which may indicate training-induced enhancement of face detection and activation of identity-specific representations. Thus, neuronal correlates of face processing are plastic in older age, and can be modulated by caricature training., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: None declared.

Older adults show higher dual task performance decrements than younger adults. While this is assumed to be related to attentional capacity reductions, the precise affected functions are not specified. Such specification is, however, possible based on the "theory of visual attention" (TVA) which allows for modeling of distinct attentional capacity parameters. Furthermore, it is unclear whether older adults show qualitatively different attentional effects or whether they show the same effects as younger adults experience under more challenging conditions. By varying the complexity of the secondary task, it is possible to address this question. In our study, participants performed a verbal whole report of briefly presented letter arrays. TVA-based fitting of report performance delivered parameters of visual threshold t 0 , processing speed C , and visual short-term memory (VSTM) storage capacity K . Furthermore, participants performed a concurrent motor task consisting of continuous tapping of a (simple or complex) sequence. Both TVA and tapping tasks were performed under single and dual task conditions. Two groups of 30 younger adults each performed either the simple or complex tapping, and a group of 30 older adults performed the simple tapping condition. In older participants, VSTM storage capacity declined under dual task conditions. While no such effect was found in younger subjects performing the simple tapping sequence under dual task conditions, the younger group performing the complex tapping task under dual task conditions also showed a significant VSTM capacity reduction. Generally, no significant effect on other TVA parameters or on tapping accuracy was found. Comparable goodness-of-fit measures were obtained for the TVA modeling data in single and dual tasks, indicating that tasks were executed in a qualitatively similar, continuous manner, although quantitatively less efficiently under dual- compared to single-task conditions. Taken together, our results show that the age-specific effects of motor-cognitive dual task interference are reflected by a stronger decline of VSTM storage capacity. They support an interpretation of VSTM as central attentional capacity, which is shared across visual uptake and concurrent motor performance. Capacity limits are reached earlier, and already under lower motor task complexity, in older compared to younger adults.

We present a case of a patient with acute wrist drop caused by radial nerve torsion. NCS showed axonal lesion of the radial nerve. High-resolution ultrasound was able to visualize a constriction of the radial nerve. Nerve torsion is a rare differential diagnosis to Saturday night palsy. The patient was subjected to early surgical intervention and showed a favorable outcome in follow-up. Thus, high-resolution ultrasound may subject these patients early to surgical therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

There is a need for easy-to-use molecular assays for diagnosis of invasive meningococcal disease. Here, we report the rapid identification of Neisseria meningitidis in a cerebrospinal fluid sample from a patient with purulent meningitis using a commercially available loop-mediated isothermal amplification assay, resulting in a prompt de-escalation of the initial empiric antibiotic therapy.

While there is a growing body of evidence regarding the behavioral and neurofunctional changes in response to the longitudinal delivery of transcranial direct current stimulation (tDCS), there is limited evidence regarding its structural effects. Therefore, the present study was intended to investigate the effect of repeatedly applied anodal tDCS over the primary somatosensory cortex on the gray matter (GM) and white matter (WM) compartment of the brain. Structural tDCS effects were, moreover, related to effects evidenced by functional imaging and behavioral assessment. tDCS was applied over the course of 5 days in 25 subjects with concomitant assessment of tactile acuity of the right and left index finger as well as imaging at baseline, after the last delivery of tDCS and at follow-up 4 weeks thereafter. Irrespective of the stimulation condition (anodal vs. sham), voxel-based morphometry revealed a behaviorally relevant decrease of GM in the precuneus co-localized with a functional change of its activity. Moreover, there was a decrease in GM of the bilateral lingual gyrus and the right cerebellum. Diffusion tensor imaging analysis showed an increase of fractional anisotropy exclusively in the tDCS anodal condition in the left frontal cortex affecting the final stretch of a somatosensory decision making network comprising the middle and superior frontal gyrus as well as regions adjacent to the genu of the corpus callosum. Thus, this is the first study in humans to identify structural plasticity in the GM compartment and tDCS-specific changes in the WM compartment in response to somatosensory learning., (© 2018 Wiley Periodicals, Inc.)

Temporary functional deafferentation (TFD) by an anesthetic cream on the stroke-affected forearm was shown to improve sensorimotor abilities of stroke patients. The present study investigated different predictors for sensorimotor improvements during TFD and indicated outcome differences between patients grouped in subcortical lesions only and lesions with any cortical involvement. Thirty-four chronic stroke patients were temporarily deafferented on the more affected forearm by an anesthetic cream. Somatosensory performance was assessed using von Frey Hair and grating orientation task; motor performance was assessed by a shape-sorter-drum task. Seven potential predictors were entered into three linear multiple regression models. Furthermore, effects of TFD on outcome variables for the two groups (cortical versus subcortical lesion) were compared. Sex and sensory deficit were significant predictors for changes in motor function while age accounted for changes in grating orienting task. Males, patients with a stronger sensory deficit, and older patients profited more. None of the potential predictors made significant contributions to changes in threshold for touch. Furthermore, there were no differences in sensorimotor improvement between lesion site groups. The effects of TFD together with the low predictability of the investigated parameters suggest that characteristics of patients alone are not suitable to exclude some patients from TFD.

Based on the topographic distribution of α-synuclein-enriched Lewy bodies, it has been hypothesized that Parkinson's disease may start in the gastrointestinal tract and gain access to the central nervous system via the vagus nerve. Since ultrasonography is a powerful tool to study peripheral nerve disturbances, we conducted ultrasonography of the vagus nerve in 32 patients with Parkinson's disease, 15 disease controls and 15 healthy controls. The cross-sectional area and echogenicity measured on transverse scans of the vagus nerve did not differ significantly between these groups. Therefore, the observed intraneuronal changes in Parkinson's disease are not associated with ultrasonographic disruptions of the vagus nerve integrity. HIGHLIGHTS We studied ultrasonography of the vagus nerve in 32 patients with Parkinson's disease and in 15 disease controls and 15 healthy controls.The sonographic cross-sectional area measured using high-frequency linear array transducers did not differ significantly between both groups.Ultrasonography of the vagal nerve does not reflect cellular damage caused by α-synuclein-enriched Lewy bodies in nerves of patients with Parkinson's disease.

Adverse prenatal environmental influences to the developing fetus are associated with mental and cardiovascular disease in later life. Universal developmental characteristics such as self-organization, pattern formation, and adaptation in the growing information processing system have not yet been sufficiently analyzed with respect to description of normal fetal development and identification of developmental disturbances. Fetal heart rate patterns are the only non-invasive order parameter of the developing autonomic brain available with respect to the developing complex organ system. The objective of the present study was to investigate whether universal indices, known from evolution and phylogeny, describe the ontogenetic fetal development from 20 weeks of gestation onwards. By means of a 10-fold cross-validated data-driven multivariate regression modeling procedure, relevant indices of heart rate variability (HRV) were explored using 552 fetal heart rate recordings, each lasting over 30 min. We found that models which included HRV indices of increasing fluctuation amplitude, complexity and fractal long-range dependencies largely estimated the maturation age (coefficients of determination 0.61-0.66). Consideration of these characteristics in prenatal care may not only have implications for early identification of developmental disturbances, but also for the development of system-theory-based therapeutic strategies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Transfer learning is an immanent feature of perceptual learning. Yet, despite the increasingly widespread application of transcranial direct current stimulation (tDCS) to study learning, transfer effects in response to tDCS have not been studied. Therefore, the present study investigated the transfer of tactile acuity evoked by repeatedly applied anodal tDCS over the left primary somatosensory cortex (S1) over the course of five days from the dominant (right) to the non-dominant (left) index finger (IF). There was a complete transfer of improvement of the right IF to its contralateral homologue by follow-up four weeks later. Changes in tactile acuity of the left IF in the tDCS anodal condition were accompanied by a significant longitudinal change in functional connectivity between the left S1 and the right secondary somatosensory cortex (S2) assessed at day five of tDCS delivery and four week later. Moreover, we observed a close link between tactile acuity and (changes of) functional connectivity of the right S2 in the tDCS anodal condition identifying the S2 as neural correlate to mediate the transfer of tDCS effects in the somatosensory domain. These findings provide unprecedented evidence of transfer effects evoked by tDCS, implicate the S2 in somatosensory transfer learning and provide evidence in support of models of perceptual learning allocating learning to the reweighting of connections between different levels of processing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH., Methods and Results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03)., Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

We describe the case of a 34-year-old patient presenting with the unique combination of bilateral vestibulopathy in combination with noise- and pressure-induced nystagmus. Bilateral vestibular dysfunction was demonstrated by pathological results in video-based head impulse testing as well as in caloric testing. In contrast, cervical vestibular-evoked myogenic potentials were normal, demonstrating normal sacculus function. Due to the positive Tullio phenomenon, semicircular dehiscence syndrome was excluded. Recently, this symptom combination was related to the histopathological finding of vestibular atelectasis., Level of Evidence: NA.Laryngoscope, 128:1223-1225, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Ruminating about sleep problems and negatively valenced thinking play a key role in the maintenance of sleep complaints in patients with insomnia. Based on associative learning principles, we hypothesized that repeated co-occurrence of negative thoughts (unconditioned stimulus) and the bedroom environment (conditioned stimulus) results in automatic negative affective responses towards the bed (conditioned response). Twenty-two insomniacs and 22 good sleepers performed a Single-Target Implicit Association Test measuring the strength of automatically triggered affective responses towards the bed. Results revealed a significant group difference, indicating a stronger negative affective response towards the bed in patients with insomnia. No correlations were found between the strength of negative affective responses towards the bed and subjective measures of sleep quality. As it might increase the stress experience further during bedtime, automatic negative responses towards the bed are likely to represent an additional factor accounting for the development and maintenance of sleep disorders and represent a potential target for therapeutic interventions., (© 2017 European Sleep Research Society.)

Müller cells are critical for retinal function and neuronal survival but can become detrimental in response to retinal ischemia and increased oxidative stress. Elevated oxidative stress increases expression of the mitochondrial enzyme frataxin in the retina, and its overexpression is neuroprotective after ischemia. Whether frataxin expression in Müller cells might improve their function and protect neurons after ischemia is unknown. The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo. Retinal ischemia/reperfusion was induced in mice overexpressing frataxin in Müller cells by transient elevation of intraocular pressure. Retinal ganglion cells survival was determined 14 days after lesion. Expression of frataxin, antioxidant enzymes, growth factors and inflammation markers was determined with qRT-PCR, Western blotting and immunohistochemistry 24 hours after lesion. Following lesion, there was a 65% increase in the number of surviving RGCs in frataxin overexpressing mice. Improved survival was associated with increased expression of the antioxidant enzymes Gpx1 and Sod1 as well as the growth factors Cntf and Lif. Additionally, microglial activation was decreased in these mice. Therefore, support of Müller cell function constitutes a feasible approach to reduce neuronal degeneration after ischemia.

The pathophysiology of amyotrophic lateral sclerosis (ALS) is particularly challenging due to the heterogeneity of its clinical presentation and the diversity of cellular, molecular and genetic peculiarities involved. Molecular insights unveiled several novel genetic factors to be inherent in both familial and sporadic disease entities, whose characterizations in terms of phenotype prediction, pathophysiological impact and putative prognostic value are a topic of current researches. However, apart from genetically well-defined high-confidence and other susceptibility loci, the role of DNA damage and repair strategies of the genome as a whole, either elicited as a direct consequence of the underlying genetic mutation or seen as an autonomous parameter, in the initiation and progression of ALS, and the different cues involved in either process are still incompletely understood. This mini review summarizes current knowledge on DNA alterations and counteracting DNA repair strategies in ALS pathology and discusses the putative role of unconventional DNA entities including transposable elements and extrachromosomal circular DNA in the disease process. Focus is set on SOD1-related pathophysiology, with extension to FUS, TDP-43 and C9ORF72 mutations. Advancing our knowledge in the field will contribute to an improved understanding of this relentless disease, for which therapeutic options others than symptomatic approaches are almost unavailable., Competing Interests: None declared

In recent years, considerable progress has been achieved in deciphering the cellular and network functions of GABAergic transmission in the intact developing brain. First, in vivo studies in non-mammalian and mammalian species confirmed the long-held assumption that GABA acts as a mainly depolarizing neurotransmitter at early developmental stages. At the same time, GABAergic transmission was shown to spatiotemporally constrain spontaneous cortical activity, whereas firm evidence for GABAergic excitation in vivo is currently missing. Second, there is a growing body of evidence indicating that depolarizing GABA may contribute to the activity-dependent refinement of neural circuits. Third, alterations in GABA actions have been causally linked to developmental brain disorders and identified as potential targets of timed prophylactic interventions. In this article, we review these major recent findings and argue that both depolarizing and inhibitory GABA actions may be crucial for physiological brain maturation.

Background/Introduction: Current telestroke network consultations are focused on decision-making in the hyperacute stage of stroke management. The two main questions in telestroke consultations are whether thrombolysis should be initiated and whether the patient should be transferred to a hub hospital. Although guidelines exist for initiating intravenous thrombolytic therapy, the question of whether patients should be transferred is far more elusive., Materials and Methods: In this study, we investigated the factors involved in the decision to transfer stroke patients to a hub hospital. We were particularly interested in identifying factors that promote or impede the transfer of patients. We enrolled 1,615 cases of telestroke consultation of the University Hospital Jena., Results: The two main factors that independently influenced the probability of transferring a patient were the patient's age and the identification of a proximal vessel occlusion. Interestingly, factors such as the severity of symptoms and the time elapsed from symptom onset were not found to have an independent influence on the decision to transfer a patient. The transfer of most patients was justified by the possibility of performing interventional reperfusion therapy., Discussion: We discuss the effectiveness of the current decision-making process and possible ways to improve decision-making for a more effective selection of patients who would benefit from transfer., Conclusion: The decision-making process to a transfer patient is not standardized and constitutes a trade-off between the intention to treat all possible patients while avoiding the transfer of patients without treatment options.

Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing.

The analysis and interpretation of somatosensory information are performed by a complex network of brain areas located mainly in the parietal cortex. Somatosensory deficits are therefore a common impairment following lesions of the parietal lobe. This chapter summarizes the clinical presentation, examination, prognosis, and therapy of sensory deficits, along with current knowledge about the anatomy and function of the somatosensory system. We start by reviewing how somatosensory signals are transmitted to and processed by the parietal lobe, along with the anatomic and functional features of the somatosensory system. In this context, we highlight the importance of the thalamus for processing somatosensory information in the parietal lobe. We discuss typical patterns of somatosensory deficits, their clinical examination, and how they can be differentiated through a careful neurologic examination that allows the investigator to deduce the location and size of the underlying lesion. In the context of adaption and rehabilitation of somatosensory functions, we delineate the importance of somatosensory information for motor performance and the prognostic evaluation of somatosensory deficits. Finally, we review current rehabilitation approaches for directing cortical reorganization in the appropriate direction and highlight some challenging questions that are unexplored in the field., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: To evaluate if weather or changes in weather are risk factors for Bell's palsy (BP) as exposure to draught of cold air has been popularly associated with the occurrence of BP., Methods: Using a multicenter hospital-based case-crossover study, we analyzed the association between ambient temperature, atmospheric pressure, relative air humidity or their 24 h changes and the risk for BP in 825 patients or subgroups., Results: One day following a 24 h increase in atmospheric pressure of more than 6 hPa, the risk for BP increased by 35% (OR 1.35; 95% CI 1.03-1.78) in the overall population. The risk for BP more than doubled in patients with diabetes mellitus after rapid variations in ambient temperature, independent of the direction (temperature decrease > 2.25°C; OR 2.15; 95% CI 1.08-4.25; temperature increase between 0.75 and 2.25°C; OR 2.88; 95% CI 1.63-5.10)., Conclusions: Our findings support the hypothesis of an association between certain weather conditions and the risk for BP with acute changes in atmospheric pressure and ambient temperature as the main risk factors. Additionally, contrasting results for risk of BP after temperature changes in the diabetic and non-diabetic subgroups support the paradigm of a diabetic facial palsy as a distinct disease entity., (© 2018 S. Karger AG, Basel.)

Acute stress-induced reduction of uterine blood flow (UBF) is an indirect mechanism of maternal-fetal stress transfer during late gestation. Effects of chronic psychosocial maternal stress (CMS) during early gestation, as may be experienced by many working women, on this stress signaling mechanism are unclear. We hypothesized that CMS in sheep during early gestation augments later acute stress-induced decreases of UBF, and aggravates the fetal hormonal, cardiovascular, and metabolic stress responses during later development. Six pregnant ewes underwent repeated isolation stress (CMS) between 30 and 100 days of gestation (dGA, term: 150 dGA) and seven pregnant ewes served as controls. At 110 dGA, ewes were chronically instrumented and underwent acute isolation stress. The acute stress decreased UBF by 19% in both the CMS and control groups (p < .05), but this was prolonged in CMS versus control ewes (74 vs. 30 min, p < .05). CMS increased fetal circulating baseline and stress-induced cortisol and norepinephrine concentrations indicating a hyperactive hypothalamus-pituitary-adrenal (HPA)-axis and sympathetic-adrenal-medullary system. Increased fetal norepinephrine is endogenous as maternal catecholamines do not cross the placenta. Cortisol in the control but not in the CMS fetuses was correlated with maternal cortisol blood concentrations; these findings indicate: (1) no increased maternal-fetal cortisol transfer with CMS, (2) cortisol production in CMS fetuses when the HPA-axis is normally inactive, due to early maturation of the fetal HPA-axis. CMS fetuses were better oxygenated, without shift towards acidosis compared to the controls, potentially reflecting adaptation to repeated stress. Hence, CMS enhances maternal-fetal stress transfer by prolonged reduction in UBF and increased fetal HPA responsiveness.

Objectives: To determine the inpatient management for patients with acute idiopathic facial palsy (IFP) in Thuringia, Germany., Design: Population-based study., Setting: All inpatients with IFP in all hospitals with departments of otolaryngology and neurology in 2012, in the German federal state, Thuringia., Main Outcome Measures: Patients' characteristics and treatment were compared between departments, and the probability of recovery was tested., Results: A total of 291 patients were mainly treated in departments of otolaryngology (55%) and neurology (36%). Corticosteroid treatment was the predominant therapy (84.5%). The probability to receive a facial nerve grading (odds ratio [OR=12.939; 95% confidence interval [CI]=3.599 to 46.516), gustatory testing (OR=6.878; CI=1.064 to 44.474) and audiometry (OR=32.505; CI=1.485 to 711.257) was significantly higher in otolaryngology departments, but lower for cranial CT (OR=0.192; CI=0.061 to 0.602), cerebrospinal fluid examination (OR=0.024; CI=0.006 to 0.102). A total of 131 patients (45%) showed a recovery to House-Brackmann grade≤II. A pathological stapedial reflex test (Hazard ratio [HR]=0.416; CI=0.180 to 0.959) was the only independent diagnostic predictor of worse outcome. Prednisolone dose >500 mg (HR=0.579; CI 0.400 to 0.838) and no adjuvant physiotherapy (HR=0.568; CI=0.407 to 0.794) were treatment-related predictors of worse outcome., Conclusions: Inpatient treatment of IFP seems to be highly variable in daily practice, partly depending on the treating discipline and despite the availability of evidence-based guidelines. The population-based recovery rate was worse than reported in clinical trials., (© 2017 John Wiley & Sons Ltd.)

Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene ( NR3C1 ) and imprinting control region (ICR) of IGF2 and H19 genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of NR3C1 affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of IGF2/H19 affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different Nr3c1 promoters and Igf2/H19 ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the Nr3c1 CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, Nr3c1 predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. Igf2/H19 ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of Nr3c1 in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic-pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat Nr3c1 and Igf2/H19 during aging that are tissue and sex specific., (Copyright © 2017 the American Physiological Society.)

Aberrations in intracellular calcium (Ca 2+ ) have been well established within amyotrophic lateral sclerosis (ALS), a severe motor neuron disease. Intracellular Ca 2+ concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca 2+ cycle (ERMCC). The ER supplies Ca 2+ to the mitochondria at close contacts between the two organelles, i.e. the mitochondria-associated ER membranes (MAMs). The Sigma 1 receptor (Sig1R) is enriched at MAMs, where it acts as an inter-organelle signaling modulator. However, its impact on intracellular Ca 2+ at the cellular level remains to be thoroughly investigated. Here, we used cultured embryonic mice spinal neurons to investigate the influence of Sig1R activation on intracellular Ca 2+ homeostasis in the presence of G93A hSOD1 (G93A), an established ALS-causing mutation. Sig1R expression was increased in G93A motor neurons relative to non-transgenic (nontg) controls. Furthermore, we demonstrated significantly reduced bradykinin-sensitive intracellular Ca 2+ stores in G93A spinal neurons, which were normalized by the Sig1R agonist SA4503. Moreover, SA4503 accelerated cytosolic Ca 2+ clearance following a) AMPAR activation by kainate and b) IP 3 R-mediated ER Ca 2+ release following bradykinin stimulation in both genotypes. PRE-084 (another Sig1R agonist) did not exert any significant effects on cytosolic Ca 2+ . Both Sig1R expression and functionality were altered by the G93A mutation, indicating the centrality of Sig1R in ALS pathology. Here, we showed that intracellular Ca 2+ shuttling can be manipulated by Sig1R activation, thus demonstrating the value of using the pharmacological manipulation of Sig1R to understand Ca 2+ homeostasis., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Stroke significantly stimulates neurogenesis in the adult dentate gyrus, though the functional role of this postlesional response is mostly unclear. Recent findings suggest that newborn neurons generated in the context of stroke may fail to correctly integrate into pre-existing networks. We hypothesized that increased neurogenesis in the dentate gyrus following stroke is associated with aberrant neurogenesis and impairment of hippocampus-dependent memory. To address these questions we used the middle cerebral artery occlusion model (MCAO) in mice. Animals were housed either under standard conditions or with free access to running wheels. Newborn granule cells were labelled with the thymidine analoque EdU and retroviral vectors. To assess memory performance, we employed a modified version of the Morris water maze (MWM) allowing differentiation between hippocampus dependent and independent learning strategies. Newborn neurons were morphologically analyzed using confocal microscopy and Neurolucida system at 7 weeks. We found that neurogenesis was significantly increased following MCAO. Animals with MCAO needed more time to localize the platform and employed less hippocampus-dependent search strategies in MWM versus controls. Confocal studies revealed an aberrant cell morphology with basal dendrites and an ectopic location (e.g. hilus) of new granule cells born in the ischemic brain. Running increased the number of new neurons but also enhanced aberrant neurogenesis. Running, did not improve the general performance in the MWM but slightly promoted the application of precise spatial search strategies. In conclusion, ischemic insults cause hippocampal-dependent memory deficits which are associated with aberrant neurogenesis in the dentate gyrus indicating ischemia-induced maladaptive plasticity in the hippocampus.

Mutations in the human Cu/Zn superoxide dismutase type-1 (hSOD1) gene are common in familial amyotrophic lateral sclerosis (fALS). The pathophysiology has been linked to, e.g., organelle dysfunction, RNA metabolism and oxidative DNA damage conferred by SOD1 malfunction. However, apart from metabolically evoked DNA oxidation, it is unclear whether severe genotoxicity including DNA single-strand breaks (SSBs) and double-strand breaks (DSBs), originates from loss of function of nuclear SOD1 enzyme. Factors that endogenously interfere with DNA integrity and repair complexes in hSOD1-mediated fALS remain similarly unexplored. In this regard, uncontrolled activation of transposable elements (TEs) might contribute to DNA disintegration and neurodegeneration. The aim of this study was to elucidate the role of the fALS-causing hSOD1G93A mutation in the generation of severe DNA damage beyond well-characterized DNA base oxidation. Therefore, DNA damage was assessed in spinal tissue of hSOD1G93A-overexpressing mice and in corresponding motor neuron-enriched cell cultures in vitro. Overexpression of the hSOD1G93A locus did not change the threshold for severe DNA damage per se. We found that levels of SSBs and DSBs were unaltered between hSOD1G93A and control conditions, as demonstrated in post-mitotic motor neurons and in astrocytes susceptible to replication-dependent DNA breakage. Analogously, parameters indicative of DNA damage response processes were not activated in vivo or in vitro. Evidence for a mutation-related elevation in TE activation was not detected, in accordance with the absence of TAR DNA binding protein 43 (TDP-43) proteinopathy in terms of cytoplasmic mislocation or nuclear loss, as nuclear TDP-43 is supposed to silence TEs physiologically. Conclusively, the superoxide dismutase function of SOD1 might not be required to preserve DNA integrity in motor neurons, at least when the function of TDP-43 is unaltered. Our data establish a foundation for further investigations addressing functional TDP-43 interaction with ALS-relevant genetic mutations.

Objective: Most epileptic seizures occur unexpectedly and independently of known risk factors. We aimed to evaluate the clinical significance of patients' perception that weather is a risk factor for epileptic seizures., Methods: Using a hospital-based, bidirectional case-crossover study, 604 adult patients admitted to a large university hospital in Central Germany for an unprovoked epileptic seizure between 2003 and 2010 were recruited. The effect of atmospheric pressure, relative air humidity, and ambient temperature on the onset of epileptic seizures under temperate climate conditions was estimated., Results: We found a close-to-linear negative correlation between atmospheric pressure and seizure risk. For every 10.7 hPa lower atmospheric pressure, seizure risk increased in the entire study population by 14% (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.01-1.28). In patients with less severe epilepsy treated with one antiepileptic medication, seizure risk increased by 36% (1.36, 1.09-1.67). A high relative air humidity of >80% increased seizure risk in the entire study population by up to 48% (OR 1.48, 95% CI 1.11-1.96) 3 days after exposure in a J-shaped association. High ambient temperatures of >20°C decreased seizure risk by 46% in the overall study population (OR 0.54, 95% CI 0.32-0.90) and in subgroups, with the greatest effects observed in male patients (OR 0.33, 95% CI 0.14-0.74)., Significance: Low atmospheric pressure and high relative air humidity are associated with an increased risk for epileptic seizures, whereas high ambient temperatures seem to decrease seizure risk. Weather-dependent seizure risk may be accentuated in patients with less severe epilepsy. Our results require further replication across different climate regions and cohorts before reliable clinical recommendations can be made., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Objective: To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase., Methods: We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters., Results: pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement., Conclusions: In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration., Classification of Evidence: This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS., (© 2017 American Academy of Neurology.)

We often close our eyes to improve perception. Recent results have shown a decrease of perception thresholds accompanied by an increase in somatosensory activity after eye closure. However, does somatosensory spatial discrimination also benefit from eye closure? We previously showed that spatial discrimination is accompanied by a reduction of somatosensory activity. Using magnetoencephalography, we analyzed the magnitude of primary somatosensory (somatosensory P50m) and primary auditory activity (auditory P50m) during a one-back discrimination task in 21 healthy volunteers. In complete darkness, participants were requested to pay attention to either the somatosensory or auditory stimulation and asked to open or close their eyes every 6.5 min. Somatosensory P50m was reduced during a task requiring the distinguishing of stimulus location changes at the distal phalanges of different fingers. The somatosensory P50m was further reduced and detection performance was higher during eyes open. A similar reduction was found for the auditory P50m during a task requiring the distinguishing of changing tones. The function of eye closure is more than controlling visual input. It might be advantageous for perception because it is an effective way to reduce interference from other modalities, but disadvantageous for spatial discrimination because it requires at least one top-down processing stage., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Aim: Antenatal glucocorticoids are used to accelerate foetal lung maturation in babies threatened with premature labour. We examined the influence of glucocorticoids on functional and structural maturation of the central somatosensory pathway in foetal sheep. Somatosensory-evoked potentials (SEP) reflect processing of somatosensory stimuli. SEP latencies are determined by afferent stimuli transmission while SEP amplitudes reveal cerebral processing., Methods: After chronic instrumentation of foetal sheep, mothers received saline (n = 9) or three courses of betamethasone (human equivalent dose of 2 × 110 μg kg -1 betamethasone i.m. 24 h apart, n = 12) at 0.7, 0.75 and 0.8 of gestational age. Trigeminal SEP were evoked prior to, 4 and 24 h after each injection and at 0.8 of gestational age before brains were histologically processed., Results: Somatosensory-evoked potentials were already detectable at 0.7 of gestation age. The early and late responses N20 and N200 were the only reproducible peaks over the entire study period. With advancing gestational age, SEP latencies decreased but amplitudes remained unchanged. Acutely, betamethasone did not affect SEP latencies and amplitudes 4 and 24 h following administration. Chronically, betamethasone delayed developmental decrease in the N200 but not N20 latency by 2 weeks without affecting amplitudes. In parallel, betamethasone decreased subcortical white matter myelination but did not affect network formation and synaptic density in the somatosensory cortex., Conclusion: Somatosensory stimuli are already processed by the foetal cerebral cortex at the beginning of the third trimester. Subsequent developmental decrease in SEP latencies suggests ongoing maturation of afferent sensory transmission. Antenatal glucocorticoids affect structural and functional development of the somatosensory system with specific effects at subcortical level., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)