Plasticity in healthy old age : a multi-domain training approach

Aging has an impact on people’s social, cognitive, and physical functioning. Despite great individual variability, healthy aging occurs along with declines in the maximal performance of several cognitive abilities including spatial navigation and memory, visuomotor skills, and executive functions, while other abilities are spared or even improve. An increasing number of older adults fears age-related losses that affect quality of life and independent functioning. Therefore, maintaining cognitive abilities is of interest from both an individual’s perspective and from a societal one since the demographic change leads to the need of keeping older adults in the workplace. Plasticity refers to the malleability of cognitive and neural functioning. This malleability is preserved across the adult lifespan until very old age and is known to be exploited by training. Considerable scientific effort has been put into finding effective interventions to improve and stabilize cognitive and brain functioning during aging. However, evidence for domain-general and long-lasting improvements has been sparse, and the mechanisms of cognitive training are not well understood. The present thesis focuses on multi-domain training, a training approach that combines exercising cognitive, physical, and social abilities. Thus, it has the potential to increase each trained domain as well as the ability to orchestrate multiple domains. First, available multi-domain training studies are reviewed. This literature review concludes that previous multi-domain training approaches have not been significantly informative regarding the impact of a particular type of multi-domain training on transfer. To fill this gap, a novel training tool has been developed. This novel training tool, called “Hotel Plastisse”, is introduced secondly. “Hotel Plastisse” is an iPad-based training specifically designed to compare the simultaneous training of three cognitive functions (multi-domain training) to the training of each single cognitive function (single-domain training). The trained domains are clearly defined and separable from each other. Thereby, training-related improvements can be related to transfer in a theoretically informed way. Furthermore, the training environment is designed as a motivating learning environment in a virtual hotel, incorporating an adaptive difficulty algorithm and providing detailed feedback. These are design aspects that are increasingly recognized as critical in the training literature. Third, a cognitive training study examines near and far transfer of single-domain and multi-domain training. Eighty-four healthy older participants aged 64 to 75 years trained either inhibition, visuomotor function, or spatial navigation (single-domain training groups), or the simultaneous combination of these three functions (multi-domain training group). With respect to near transfer, the single-domain and the multi-domain training groups did not differ. With respect to far transfer, improvements on attentional control were more pronounced in the multi- domain training group than in the single-domain training group. Furthermore, independent of training group, individuals with lower baseline performance showed higher training-related change on the transfer test battery compared to individuals with higher baseline performance. Six months after training, training-related improvements remained stable. The findings show that multi-domain training enhances functions that involve handling several different tasks at the same time, which is an everyday challenge especially for older people. Fourth, functional brain network characteristics are compared between three groups of participants that differed with respect to their training history (multi-domain training group, visuomotor function training group, participants with no training history). One year after training, participants underwent high-density electroencephalographic (EEG) measurement to examine expertise-related functional connectivity and small-world network characteristics during performance on the multi-domain training task. The multi-domain training group performed significantly better than the visuomotor function training group and the control group (no training history). In addition, the multi-domain training group showed enhanced and more efficient functional connectivity in a task-related network encompassing visual, motor, executive, and memory-associated brain areas. Hence, the findings show expertise-dependent differences in performance and neural network characteristics even a year after training. Taken together, the thesis presents evidence for cognitive and neural plasticity in healthy older adults induced by a simultaneous multi-domain training. Training regimes that target older adults’ ability to handle several tasks simultaneously may enhance the probability for an overlap with different situations. Future studies should take methodological approaches that allow researchers to relate inter-individual differences to training progress and transfer. In addition, neuroimaging will lead to a better understanding of the neurobiological bases of plasticity. Well-informed experimental paradigms combined with sophisticated behavioral and neuroimaging data analyses will provide further insights into the mechanisms of training- induced plastic changes in healthy aging, and will thereby advance the development of effective interventions

Multi-domain training enhances attentional control

Multi-domain cognitive training potentially increases the likelihood for an overlap in processing component with transfer tasks and everyday life, and hence is a promising training approach for older adults. To empirically test this, 84 healthy older adults aged 65 to 75 years were randomly assigned to one of three single-domain training conditions (inhibition, visuomotor function, spatial navigation) or to the simultaneous training of all three cognitive functions (multi-domain training condition). All participants trained on an iPad at home for 50 training sessions. Before and after the training, and at a six-month follow-up measurement, cognitive functioning and training transfer were assessed with a neuropsychological test battery including tests targeting the trained functions (near transfer) and transfer to executive functions (far transfer: attentional control, working memory, speed). Participants in all four training groups showed a linear increase in training performance over the 50 training sessions. Using a latent difference score model, the multi-domain training group, compared to the single-domain training groups, showed more improvement on the far transfer, executive attentional control composite. Individuals with initially lower baseline performance showed higher training-related improvements, indicating that training compensated for lower initial cognitive performance. At the six-month follow-up, performance on the cognitive test battery remained stable. This is one of the first studies that systematically investigated multi-domain training including comparable single-domain training conditions. Our findings suggest that multi-domain training enhances executive attentional control involved in handling several different tasks at the same time, an aspect in everyday life that is particularly challenging for older people

Organotypical tissue cultures from adult murine colon as an in vitro model of intestinal mucosa

Together with animal experiments, organotypical cell cultures are important models for analyzing cellular interactions of the mucosal epithelium and pathogenic mechanisms in the gastrointestinal tract. Here, we introduce a three-dimensional culture model from the adult mouse colon for cell biological investigations in an in vivo-like environment. These explant cultures were cultured for up to 2 weeks and maintained typical characteristics of the intestinal mucosa, including a high-prismatic epithelium with specific epithelial cell-to-cell connections, a basal lamina and various connective tissue cell types, as analyzed with immunohistological and electron microscopic methods. The function of the epithelium was tested by treating the cultures with dexamethasone, which resulted in a strong upregulation of the serum- and glucocorticoid-inducible kinase 1 similar to that found in vivo. The culture system was investigated in infection experiments with the fungal pathogen Candida albicans. Wildtype but not Δcph1/Δefg1-knockout Candida adhered to, penetrated and infiltrated the epithelial barrier. The results demonstrate the potential usefulness of this intestinal in vitro model for studying epithelial cell-cell interactions, cellular signaling and microbiological infections in a three-dimensional cell arrangement

The neural substrate of positive bias in spontaneous emotional processing

Even in the presence of negative information, healthy human beings display an optimistic tendency when thinking of past success and future chances, giving a positive bias to everyday's cognition. The tendency to actively select positive thoughts suggests the existence of a mechanism to exclude negative content, raising the issue of its dependence on mechanisms like those of effortful control. Using perfusion imaging, we examined how brain activations differed according to whether participants were left to prefer positive thoughts spontaneously, or followed an explicit instruction to the same effect, finding a widespread dissociation of brain perfusion patterns. Under spontaneous processing of emotional material, recruitment of areas associated with effortful attention, such as the dorsolateral prefrontal cortex, was reduced relative to instructed avoidance of negative material (F(1,58) = 26.24, p = 0.047, corrected). Under spontaneous avoidance perfusion increments were observed in several areas that were deactivated by the task, including the perigenual medial prefrontal cortex. Furthermore, individual differences in executive capacity were not associated with positive bias. These findings suggest that spontaneous positive cognitive emotion regulation in health may result from processes that, while actively suppressing emotionally salient information, differ from those associated with effortful and directed control

Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression

Background Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. Methodology/Principal Findings A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. Conclusions/Significance This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further

A Search for Coincident Neutrino Emission from Fast Radio Bursts with Seven Years of IceCube Cascade Events

This paper presents the results of a search for neutrinos that are spatially and temporally coincident with 22 unique, nonrepeating fast radio bursts (FRBs) and one repeating FRB (FRB 121102). FRBs are a rapidly growing class of Galactic and extragalactic astrophysical objects that are considered a potential source of high-energy neutrinos. The IceCube Neutrino Observatory\u27s previous FRB analyses have solely used track events. This search utilizes seven years of IceCube cascade events which are statistically independent of track events. This event selection allows probing of a longer range of extended timescales due to the low background rate. No statistically significant clustering of neutrinos was observed. Upper limits are set on the time-integrated neutrino flux emitted by FRBs for a range of extended time windows

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is &lt;10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical &amp; Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48x10-7; Bonferroni-corrected significance threshold p < 2.79x10-6). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches