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Background: Limiting the ability to engage in social interaction, aphasia increases the risk of poststroke depression and may prevent classical forms of psychotherapy. Our parallel-group, blinded-assessment, quasi-randomized controlled trial explores the feasibility and potential efficacy of intensive social interaction as a means to alleviate poststroke depression in subacute aphasia. Methods: We adopted a linguistically validated treatment program based on massed practice and conversational turn-taking (Intensive Language-Action Therapy). In a routine outpatient setting, 60 individuals with poststroke depression and subacute aphasia (0.5–6 months following left-hemispheric ischemia or hemorrhage) were assigned to Intensive Language-Action Therapy combined with standard care (Group I) or standard care alone (Group II). End points included feasibility (primary outcome) alongside change on self-report and clinician-rated measures of depression severity (co-primary outcomes: Beck’s Depression Inventory; Hamilton Rating Scale for Depression) after a 1-month treatment period (5 weekly 1-hour sessions), controlled for progress in language performance (secondary outcome: Aachen Aphasia Test, AAT). Results: 100% treatment participation demonstrated feasibility of Intensive Language-Action Therapy in poststroke depression. Analyses ( n =60) revealed significant between-group differences on the Beck’s Depression Inventory (change in Group I [95% CI]: −12.6 [±4.9]; in Group II: −5.8 [±3.2]; P =0.040) and Hamilton Rating Scale for Depression (change in Group I: −5.0 [±1.4]; in Group II: −3.3 [±1.2]; P =0.002), indicating small-to-medium effect sizes in reducing depression severity with Intensive Language-Action Therapy ( η 2 ≤0.101). No significant between-group differences emerged on expressive AAT subscales. Conclusions: Our results confirm the feasibility and potential efficacy of intensive social interaction for treatment of poststroke depression in subacute aphasia. Registration: URL: www.clinicaltrials.gov ; Unique identifier: NCT04318951.

Two studies investigating the effect of radical weight loss on brains structure and function.

Obesity and its comorbidities are linked to impaired cognitive performance, accelerated cognitive decline and neurodegenerative pathologies (Dye et al., 2017). Besides frequently reported cortical thinning and alterations in subcortical gray matter volume (Tanaka et al., 2020), obesity seems to have serious repercussions on global white matter coherence and the microstructure of the brain region crucially involved in feeding behavior and metabolism, the hypothalamus (Lampe, et al., 2019; Schwartz et al., 2000; Thomas, et al. 2019). A dominant explanation for obesity-related structural and functional alterations and associated cognitive impairments is that a high-fat fat diet and accumulation of visceral fat set off a metabolic and immunological cascade which may result in systemic chronic low-grade inflammation as well as neuroinflammation attacking the central nervous system (Leigh & Morris, 2020). Bariatric surgery encompasses procedures that surgically modify the stomach and the intestines to induce weight loss by food restriction and nutrients malabsorption. To date, it is the most effective intervention to reliably induce considerable reduction of excess body fat and improve metabolic risk factors. It has been shown to reduce the characteristic low-grade inflammation and, importantly, to exert positive effects on the central nervous system. Widespread effects on brain structure and function are documented by a growing body of literature (Nota et al., 2020). This project aims to determine whether surgical interventions for morbidly obese individuals lead to a recovery in microstructure of major white matter tracts and the hypothalamus, comparing a group of bariatric patients with a waiting-list control group. The overarching goal will be to characterize the mechanisms by which the proposed recovery is driven and the time course in which positive effects unfold.

Supplementation with spermidine may support healthy aging, but elevated spermidine tissue levels were shown to be an indicator of Alzheimer's disease (AD).Data from 659 participants (age range: 21-81 years) of the population-based Study of Health in Pomerania TREND were included. We investigated the association between spermidine plasma levels and markers of brain aging (hippocampal volume, AD score, global cortical thickness [CT], and white matter hyperintensities [WMH]).Higher spermidine levels were significantly associated with lower hippocampal volume (ß = -0.076; 95% confidence interval [CI]: -0.13 to -0.02; q = 0.026), higher AD score (ß = 0.118; 95% CI: 0.05 to 0.19; q = 0.006), lower global CT (ß = -0.104; 95% CI: -0.17 to -0.04; q = 0.014), but not WMH volume. Sensitivity analysis revealed no substantial changes after excluding participants with cancer, depression, or hemolysis.Elevated spermidine plasma levels are associated with advanced brain aging and might serve as potential early biomarker for AD and vascular brain pathology.

INTRODUCTION: Chemotherapy-induced polyneuropathy (CIPN) and post-chemotherapy cognitive impairment (PCCI) are frequent side effects of paclitaxel treatment. CIPN/PCCI are potentially irreversible, reduce quality of life and often lead to treatment limitations, which affect patients’ outcome. We previously demonstrated that paclitaxel enhances an interaction of the Neuronal calcium sensor-1 protein (NCS-1) with the Inositol-1,4,5-trisphosphate receptor (InsP3R), which disrupts calcium homeostasis and triggers neuronal cell death via the calcium-dependent protease calpain in dorsal root ganglia neurons and neuronal precursor cells. Prophylactic treatment of rodents with lithium inhibits the NCS1-InsP3R interaction and ameliorates paclitaxel-induced polyneuropathy and cognitive impairment, which is in part supported by limited retrospective clinical data in patients treated with lithium carbonate at the time of chemotherapy. Currently no data are available from a prospective clinical trial to demonstrate its efficacy. METHODS AND ANALYSIS: The PREPARE study will be conducted as a multicenter, randomized, double-blind, placebo-controlled phase-2 trial with parallel group design. N = 84 patients with breast cancer will be randomized 1:1 to either lithium carbonate treatment (targeted serum concentration 0.5–0.8 mmol/l) or placebo with sham dose adjustments as add-on to (nab-) paclitaxel. The primary endpoint is the validated Total Neuropathy Score reduced (TNSr) at 2 weeks after the last (nab-) paclitaxel infusion. The aim is to show that the lithium carbonate group is superior to the placebo group, meaning that the mean TNSr after (nab-) paclitaxel is lower in the lithium carbonate group than in the placebo group. Secondary endpoints include: (1) severity of CIPN, (2) amount and dose of pain medication, (3) cumulative dose of (nab-) paclitaxel, (4) patient-reported symptoms of CIPN, quality of life and symptoms of anxiety and depression, (5) severity of cognitive impairment, (6) hippocampal volume and changes in structural/functional connectivity and (7) serum Neurofilament light chain protein concentrations. ETHICS AND DISSEMINATION: The study protocol was approved by the Berlin ethics committee (reference: 21/232 – IV E 10) and the respective federal agency (Bundesinstitut für Arzneimittel und Medizinprodukte, reference: 61-3910-4044771). The results of the study will be published in peer-reviewed medical journals as well as presented at relevant (inter)national conferences. CLINICAL TRIAL REGISTRATION: [https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00027165], identifier [DRKS00027165].

BackgroundOscillatory rhythms during sleep such as slow oscillations (SO) and spindles, and most importantly their coupling, are thought to underlie processes of memory consolidation. External slow oscillatory transcranial direct current stimulation (so-tDCS) with a frequency of 0.75 Hz has been shown to improve this coupling and memory consolidation, however, effects varied quite markedly between individuals, studies, and species. Here, we aimed to determine how precisely the frequency of stimulation has to match the naturally occurring SO frequency in individuals to optimally improve SO-spindle coupling. Moreover, we systematically tested stimulation durations necessary to induce changes.MethodsWe addressed these questions by comparing so-tDCS with individualized frequency to standardized frequency of 0.75 Hz in a within-subject design with 28 older participants during napping while systematically varying stimulation train durations between 30 s, 2 min, and 5 min.ResultsStimulation trains as short as 30 s were sufficient to modulate the coupling between SOs and spindle activity. Contrary to our expectations, so-tDCS with standardized frequency indicated stronger aftereffects with regard to SO-spindle coupling compared to individualized frequency. Angle and variance of spindle maxima occurrence during the SO cycle were similarly modulated.ConclusionIn sum, short stimulation trains were sufficient to induce significant changes in sleep physiology allowing for more trains of stimulation, which provides methodological advantages and possibly even larger behavioral effects in future studies. With regard to individualized stimulation frequency, further options of optimization need to be investigated, such as closed-loop stimulation to calibrate stimulation frequency to the SO frequency at time of stimulation onset.Significance statementApplication of slow oscillatory transcranial direct current stimulation during sleep has been shown to enhance specific memory-relevant sleep parameters and memory performance after sleep, albeit with a high degree of variability. Here, we systematically explored two major stimulation parameters possibly accounting for this variability in humans: frequency and duration of stimulation. We found, contrary to our expectations, standardized frequency stimulation with 0.75 Hz being superior to individualized frequency stimulation in enhancing specific sleep parameters. Moreover short stimulation trains of 30 seconds were as effective as 5 min in modulating aftereffects. These are encouraging findings, implying methodological advantages as larger quantity of aftereffects data can be obtained within the same time window, which may also lead to enhanced behavioral stimulation effects.

Gender biases are well documented in science and typically favor male scientists. In this context, a particularly pervasive gender bias is undercitation of publications authored by women, resulting in profound negative effects on academic visibility and career advancement. This bias has been well documented in fields where author gender distributions are strongly skewed towards men (e.g., astronomy, physics, neuroscience). By investigating citation practices in a field that has traditionally been more accessible to female scientists (Speech and Language Pathology, SLP), we demonstrate that gendered citation practices are mediated by author gender distribution, rather than being a universal pattern. Specifically, our results revealed a citation pattern in SLP that (a) overall tends to favor female authors, (b) persists after controlling for potential confounding factors and, (c) is particularly strong when female authors are citing publications involving female first and senior author teams. This research also implies that the implementation of effective measures to increase the number and influence of underrepresented individuals in specific fields of science may be suitable to mitigate downstream disadvantages for career advancement of either sex.

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.Demenzen sind teure Erkrankungen: die jährlichen Kosten betragen in europäischen Versorgungssystemen etwa 28.000 €/Fall mit einer starken Stadien-Abhängigkeit, davon entfallen etwa 19% auf die medizinische Versorgung. Die diagnostischen Kosten hingegen verursachen davon nur einen geringen Teil. Mit Wandel des konzeptuellen Verständnisses von Demenzerkrankungen, der Behandlungsmöglichkeiten und der Leitlinien spielen zunehmend auch Biomarker-Untersuchungen eine wichtige Rolle. Die ökonomischen Auswirkungen der Biomarker-basierten Diagnostik sind derzeit nicht sicher abschätzbar. Zur Erhebung der Kosten einer leitlinien-orientierten ätiologischen Erst-Diagnostik von kognitiven Störungen wurde eine Umfrage im Deutschen Netzwerk Gedächtnisambulanzen (DNG) durchgeführt. An 15 Expertenzentren des DNG wurden systematisch die Personalbindungszeiten für alle Prozeduren und alle beteiligten Berufsgruppen erhoben und die Personalkosten basierend auf den tarifvertraglichen Arbeitgeberkosten berechnet. Zusammen mit den Kosten für technische Untersuchungen wurden Gesamtkosten der Diagnostik für drei Szenarien abgeschätzt: Diagnostik ohne Biomarker € 633,97 €, Diagnostik mit Liquoruntersuchungen € 1.214,90 und Diagnostik mit FDG- plus Amyloid-PET € 4.740,58. Zusätzlich erfolgte eine Analyse der derzeitigen realen Kostensituation in Gedächtnisambulanzen, wobei die Personalbindungszeiten für einzelne Leistungen und die apparativen Kosten ins Verhältnis zur Häufigkeit ihrer Anwendung gesetzt wurden. Als Mittelwert aller Zentren ergeben sich dabei Gesamtkosten von € 1.394,43/Fall (Mittelwert der Personalkosten € 351,72, Mittelwert der Kosten für apparative Diagnostik € 1.042,71). Die Ergebnisse zeigen, dass eine ätiologische Diagnostik von kognitiven Störungen (Demenzen und leichte kognitive Störung) einen Ressourceneinsatz erfordert, welcher derzeit weder durch die Vergütungssysteme von Ambulanzen noch durch die vertragsärztliche Vergütung kostendeckend erstattet wird. Die Biomarker-gestützte Diagnostik dementieller und prädementieller Syndrome wird häufiger werden, wenn sie zur Indikationsstellung vor einer krankheits-modifizierenden Therapie erforderlich ist. Deshalb müssen neue Finanzierungsmodelle entwickelt werden, um die gegenwärtige Lücke in der Kostenerstattung für die ätiologische Diagnostik kognitiver Störungen zu schließen.

The global increase in neurodegenerative disorders is one of the most crucial public health issues. Oral polyamine intake was shown to improve memory performance which is thought to be mediated at least in part via increased autophagy induced in brain cells. In Alzheimer’s Disease, T-cells were identified as important mediators of disease pathology. Since autophagy is a central regulator of cell activation and cytokine production, we investigated the influence of polyamines on T-cell activation, autophagy, and the release of Th1/Th2 cytokines from blood samples of patients (n=22) with cognitive impairment or dementia in comparison to healthy controls (n=12) ex vivo. We found that spermine downregulated all investigated cytokines in a dose-dependent manner. Spermidine led to an upregulation of some cytokines for lower dosages, while high dosages downregulated all cytokines apart from upregulated IL-17A. Autophagy and T-cell activation increased in a dose-dependent manner by incubation with either polyamine. Although effects in patients were seen in lower concentrations, alterations were similar to controls. We provide novel evidence that supplementation of polyamines alters the function of T-cells. Given their important role in dementia, these data indicate a possible mechanism by which polyamines would help to prevent structural and cognitive decline in aging.

IMPORTANCE: Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline. OBJECTIVE: To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group. DESIGN, SETTING, and PARTICIPANTS: This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021. INTERVENTIONS: One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention. MAIN OUTCOMES AND MEASURES: Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed. RESULTS: A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03094546.

ZusammenfassungDemenzen sind teure Erkrankungen: die jährlichen Kosten betragen in europäischen Versorgungssystemen etwa 28.000 €/Fall mit einer starken Stadien-Abhängigkeit, davon entfallen etwa 19% auf die medizinische Versorgung. Die diagnostischen Kosten hingegen verursachen davon nur einen geringen Teil. Mit Wandel des konzeptuellen Verständnisses von Demenzerkrankungen, der Behandlungsmöglichkeiten und der Leitlinien spielen zunehmend auch Biomarker-Untersuchungen eine wichtige Rolle. Die ökonomischen Auswirkungen der Biomarker-basierten Diagnostik sind derzeit nicht sicher abschätzbar. Zur Erhebung der Kosten einer leitlinien-orientierten ätiologischen Erst-Diagnostik von kognitiven Störungen wurde eine Umfrage im Deutschen Netzwerk Gedächtnisambulanzen (DNG) durchgeführt. An 15 Expertenzentren des DNG wurden systematisch die Personalbindungszeiten für alle Prozeduren und alle beteiligten Berufsgruppen erhoben und die Personalkosten basierend auf den tarifvertraglichen Arbeitgeberkosten berechnet. Zusammen mit den Kosten für technische Untersuchungen wurden Gesamtkosten der Diagnostik für drei Szenarien abgeschätzt: Diagnostik ohne Biomarker € 633,97 €, Diagnostik mit Liquoruntersuchungen € 1.214,90 und Diagnostik mit FDG- plus Amyloid-PET € 4.740,58. Zusätzlich erfolgte eine Analyse der derzeitigen realen Kostensituation in Gedächtnisambulanzen, wobei die Personalbindungszeiten für einzelne Leistungen und die apparativen Kosten ins Verhältnis zur Häufigkeit ihrer Anwendung gesetzt wurden. Als Mittelwert aller Zentren ergeben sich dabei Gesamtkosten von € 1.394,43/Fall (Mittelwert der Personalkosten € 351,72, Mittelwert der Kosten für apparative Diagnostik € 1.042,71). Die Ergebnisse zeigen, dass eine ätiologische Diagnostik von kognitiven Störungen (Demenzen und leichte kognitive Störung) einen Ressourceneinsatz erfordert, welcher derzeit weder durch die Vergütungssysteme von Ambulanzen noch durch die vertragsärztliche Vergütung kostendeckend erstattet wird. Die Biomarker-gestützte Diagnostik dementieller und prädementieller Syndrome wird häufiger werden, wenn sie zur Indikationsstellung vor einer krankheits-modifizierenden Therapie erforderlich ist. Deshalb müssen neue Finanzierungsmodelle entwickelt werden, um die gegenwärtige Lücke in der Kostenerstattung für die ätiologische Diagnostik kognitiver Störungen zu schließen.

During slow-wave sleep, the brain is in a self-organized regime in which slow oscillations (SOs) between up- and down-states travel across the cortex. While an isolated piece of cortex can produce SOs, the brain-wide propagation of these oscillations are thought to be mediated by the long-range axonal connections. We address the mechanism of how SOs emerge and recruit large parts of the brain using a whole-brain model constructed from empirical connectivity data in which SOs are induced independently in each brain area by a local adaptation mechanism. Using an evolutionary optimization approach, good fits to human resting-state fMRI data and sleep EEG data are found at values of the adaptation strength close to a bifurcation where the model produces a balance between local and global SOs with realistic spatiotemporal statistics. Local oscillations are more frequent, last shorter, and have a lower amplitude. Global oscillations spread as waves of silence across the undirected brain graph, traveling from anterior to posterior regions. These traveling waves are caused by heterogeneities in the brain network in which the connection strengths between brain areas determine which areas transition to a down-state first, and thus initiate traveling waves across the cortex. Our results demonstrate the utility of whole-brain models for explaining the origin of large-scale cortical oscillations and how they are shaped by the connectome.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject’s age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be “safe” where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs., Clinical Neurophysiology Practice, 7, ISSN:2467-981X

Neural mechanisms of behavioral improvement induced by repeated transcranial direct current stimulation (tDCS) combined with cognitive training are yet unclear. Previously, we reported behavioral effects of a 3-day visuospatial memory training with concurrent anodal tDCS over the right temporoparietal cortex in older adults. To investigate intervention-induced neural alterations we here used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) datasets available from 35 participants of this previous study, acquired before and after the intervention. To delineate changes in whole-brain functional network architecture, we employed eigenvector centrality mapping. Gray matter alterations were analyzed using DTI-derived mean diffusivity (MD). Network centrality in the bilateral posterior temporooccipital cortex was reduced after anodal compared to sham stimulation. This focal effect is indicative of decreased functional connectivity of the brain region underneath the anodal electrode and its left-hemispheric homolog with other "relevant" (i.e., highly connected) brain regions, thereby providing evidence for reorganizational processes within the brain's network architecture. Examining local MD changes in these clusters, an interaction between stimulation condition and training success indicated a decrease of MD in the right (stimulated) temporooccipital cluster in individuals who showed superior behavioral training benefits. Using a data-driven whole-brain network approach, we provide evidence for targeted neuromodulatory effects of a combined tDCS-and-training intervention. We show for the first time that gray matter alterations of microstructure (assessed by DTI-derived MD) may be involved in tDCS-enhanced cognitive training. Increased knowledge on how combined interventions modulate neural networks in older adults, will help the development of specific therapeutic interventions against age-associated cognitive decline.