| 1. |
- Drude, Natascha Ingrid, et al.
(författare)
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Planning preclinical confirmatory multicenter trials to strengthen translation from basic to clinical research : a multi-stakeholder workshop report
- 2022
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Ingår i: Translational Medicine Communications. - : Springer Nature. - 2396-832X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Clinical translation from bench to bedside often remains challenging even despite promising preclinical evidence. Among many drivers like biological complexity or poorly understood disease pathology, preclinical evidence often lacks desired robustness. Reasons include low sample sizes, selective reporting, publication bias, and consequently inflated effect sizes. In this context, there is growing consensus that confirmatory multicenter studies -by weeding out false positives- represent an important step in strengthening and generating preclinical evidence before moving on to clinical research. However, there is little guidance on what such a preclinical confirmatory study entails and when it should be conducted in the research trajectory. To close this gap, we organized a workshop to bring together statisticians, clinicians, preclinical scientists, and meta-researcher to discuss and develop recommendations that are solution-oriented and feasible for practitioners. Herein, we summarize and review current approaches and outline strategies that provide decision-critical guidance on when to start and subsequently how to plan a confirmatory study. We define a set of minimum criteria and strategies to strengthen validity before engaging in a confirmatory preclinical trial, including sample size considerations that take the inherent uncertainty of initial (exploratory) studies into account. Beyond this specific guidance, we highlight knowledge gaps that require further research and discuss the role of confirmatory studies in translational biomedical research. In conclusion, this workshop report highlights the need for close interaction and open and honest debate between statisticians, preclinical scientists, meta-researchers (that conduct research on research), and clinicians already at an early stage of a given preclinical research trajectory.
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| 2. |
- Filevich, Elisa, et al.
(författare)
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Day2day : Investigating daily variability of magnetic resonance imaging measures over half a year
- 2017
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most studies of brain structure and function, and their relationships to cognitive ability, have relied on inter-individual variability in magnetic resonance (MR) images. Intra-individual variability is often ignored or implicitly assumed to be equivalent to the former. Testing this assumption empirically by collecting enough data on single individuals is cumbersome and costly. We collected a dataset of multiple MR sequences and behavioural covariates to quantify and characterize intra-individual variability in MR images for multiple individuals. Methods and design: Eight participants volunteered to undergo brain scanning 40-50 times over the course of 6 months. Six participants completed the full set of sessions. T1-weighted, T2*-weighted during rest, T2-weighted high-resolution hippocampus, diffusion-tensor imaging (DTI), and proton magnetic resonance spectroscopy sequences were collected, along with a rich set of stable and time-varying physical, behavioural and physiological variables. Participants did not change their lifestyle or participated in any training programs during the period of data collection. Conclusion: This imaging dataset provides a large number of MRI scans in different modalities for six participants. It enables the analysis of the time course and correlates of intra-individual variability in structural, chemical, and functional aspects of the human brain.
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| 3. |
- Fjell, Anders M., et al.
(författare)
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Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium
- 2021
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Ingår i: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 31:4, s. 1953-1969
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Tidskriftsartikel (refereegranskat)abstract
- We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.
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| 4. |
- Kühn, Simone, et al.
(författare)
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Brain areas consistently linked to individual differences in perceptual decision-making in younger as well as older adults before and after training
- 2011
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Ingår i: Journal of cognitive neuroscience. - Cambridge, Mass. : MIT Press. - 0898-929X .- 1530-8898. ; 23:9, s. 2147-2158
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Tidskriftsartikel (refereegranskat)abstract
- Perceptual decision-making performance depends on several cognitive and neural processes. Here, we fit Ratcliff's diffusion model to accuracy data and reaction-time distributions from one numerical and one verbal two-choice perceptual-decision task to deconstruct these performance measures into the rate of evidence accumulation (i.e., drift rate), response criterion setting (i.e., boundary separation), and peripheral aspects of performance (i.e., nondecision time). These theoretical processes are then related to individual differences in brain activation by means of multiple regression. The sample consisted of 24 younger and 15 older adults performing the task in fMRI before and after 100 daily 1-hr behavioral training sessions in a multitude of cognitive tasks. Results showed that individual differences in boundary separation were related to striatal activity, whereas differences in drift rate were related to activity in the inferior parietal lobe. These associations were not significantly modified by adult age or perceptual expertise. We conclude that the striatum is involved in regulating response thresholds, whereas the inferior parietal lobe might represent decision-making evidence related to letters and numbers.
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| 5. |
- Kühn, Simone, et al.
(författare)
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The dynamics of change in striatal activity following updating training
- 2013
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Ingår i: Human Brain Mapping. - : Wiley. - 1065-9471 .- 1097-0193. ; 34:7, s. 1530-1541
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Tidskriftsartikel (refereegranskat)abstract
- Increases in striatal activity have been suggested to mediate training-related improvements in working-memory ability. We investigated the temporal dynamics of changes in task-related brain activity following training of working memory. Participants in an experimental group and an active control group, trained on easier tasks of a constant difficulty in shorter sessions than the experimental group, were measured before, after about 1 week, and after more than 50 days of training. In the experimental group an initial increase of working-memory related activity in the functionally defined right striatum and anatomically defined right and left putamen was followed by decreases, resulting in an inverted u-shape function that relates activity to training over time. Activity increases in the striatum developed slower in the active control group, observed at the second posttest after more than 50 days of training. In the functionally defined left striatum, initial activity increases were maintained after more extensive training and the pattern was similar for the two groups. These results shed new light on the relation between activity in the striatum (especially the putamen) and the effects of working memory training, and illustrate the importance of multiple measurements for interpreting effects of training on regional brain activity.
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| 6. |
- Kuhn, Simone, et al.
(författare)
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The neural representation of intrusive thoughts
- 2013
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Ingår i: Social Cognitive and Affective Neuroscience. - : Oxford University Press (OUP). - 1749-5024 .- 1749-5016. ; 8:6, s. 688-693
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Tidskriftsartikel (refereegranskat)abstract
- Based on the philosophical notion that language embodies thought we investigated whether a habitual tendency for intrusive thought that younger and older participants report over a period of 100 sessions, spread out over about 6 months, is associated with brain regions related to language production. In favour of this hypothesis, we found that individual differences in habitual intrusive thoughts are correlated with activity in the left inferior frontal gyrus (IFG, Broca's area) as well as the cingulate cortex (CC) during a two-choice reaction-time task in fMRI. Participants who habitually tended to experience intrusive thoughts showed greater activity during task-free (baseline) compared to task periods in brain regions involved in language production. Task performance was unrelated to individual differences in intrusive thoughts. We conclude that intrusive thoughts may be represented in a language-like format and that individuals reporting a habitually higher tendency for intrusive thoughts may have stronger and more habitual inner speech processes.
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| 7. |
- Lövdén, Martin, et al.
(författare)
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Experience-dependent plasticity of white-matter microstructure extends into old age
- 2010
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Ingår i: Neuropsychologia. - : Elsevier BV. - 0028-3932 .- 1873-3514. ; 48:13, s. 3878-3883
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Tidskriftsartikel (refereegranskat)abstract
- Experience-dependent alterations in the human brain's white-matter microstructure occur in early adulthood, but it is unknown whether such plasticity extends throughout life. We used cognitive training, diffusion-tensor imaging (DTI), and structural MRI to investigate plasticity of the white-matter tracts that connect the left and right hemisphere of the frontal lobes. Over a period of about 180 days, 20 younger adults and 12 older adults trained for a total of one hundred and one 1-h sessions on a set of three working memory, three episodic memory, and six perceptual speed tasks. Control groups were assessed at pre- and post-test. Training affected several DTI metrics and increased the area of the anterior part of the corpus callosum. These alterations were of similar magnitude in younger and older adults. The findings indicate that experience-dependent plasticity of white-matter microstructure extends into old age and that disruptions of structural interhemispheric connectivity in old age, which are pronounced in aging, are modifiable by experience and amenable to treatment.
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| 8. |
- Lövdén, Martin, et al.
(författare)
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Spatial navigation training protects the hippocampus against age-related changes during early and late adulthood
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:3, s. 620.e9-620.e22
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Tidskriftsartikel (refereegranskat)abstract
- It is unknown whether lifestyle, including mental stimulation, and appropriate training interventions, may directly improve spatial navigation performance and its underlying neural substrates. Here we report that healthy younger and older men performing a cognitively demanding spatial navigation task every other day over 4 months display navigation-related gains in performance and stable hippocampal volumes that were maintained 4 months after termination of training. In contrast, control groups displayed volume decrements consistent with longitudinal estimates of age-related decline. Hippocampal barrier density, as indicated by mean diffusivity estimated from diffusion tensor imaging, showed a quadratic shape of increased density after training followed by a return to baseline in the right hippocampus, but declined in the control groups and in the left hippocampus. We conclude that sustained experiential demands on spatial ability protect hippocampal integrity against age-related decline. These results provide the first longitudinal evidence indicating that spatial navigation experience modifies hippocampal volumes in humans, and confirm epidemiological results suggesting that mental stimulation may have direct effects on neural integrity.
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| 9. |
- Wenger, Elisabeth, et al.
(författare)
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Cortical thickness changes following spatial navigation training in adulthood and aging
- 2012
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 59:4, s. 3389-3397
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Tidskriftsartikel (refereegranskat)abstract
- A widespread network involving cortical and subcortical brain structures forms the neural substrate of human spatial navigation. Most studies investigating plasticity of this network have focused on the hippocampus. Here, we investigate age differences in cortical thickness changes evoked by four months of spatial navigation training in 91 men aged 20-30 or 60-70 years. Cortical thickness was automatically measured before, immediately after, and four months after termination of training. Younger as well as older navigators evidenced large improvements in navigation performance that were partly maintained after termination of training. Importantly, training-related cortical thickening in left precuneus and paracentral lobule were observed in young navigators only. Thus, spatial navigation training appears to affect cortical brain structure of young adults, but there is reduced potential for experience-dependent cortical alterations in old age.
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| 10. |
- Karch, Julian D, et al.
(författare)
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Identifying predictors of within-person variance in MRI-based brain volume estimates
- 2019
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Ingår i: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 200, s. 575-589
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Tidskriftsartikel (refereegranskat)abstract
- Adequate reliability of measurement is a precondition for investigating individual differences and age-related changes in brain structure. One approach to improve reliability is to identify and control for variables that are predictive of within-person variance. To this end, we applied both classical statistical methods and machine-learning-inspired approaches to structural magnetic resonance imaging (sMRI) data of six participants aged 24-31 years gathered at 40-50 occasions distributed over 6-8 months from the Day2day study. We explored the within-person associations between 21 variables covering physiological, affective, social, and environmental factors and global measures of brain volume estimated by VBM8 and FreeSurfer. Time since the first scan was reliably associated with Freesurfer estimates of grey matter volume and total cortex volume, in line with a rate of annual brain volume shrinkage of about 1 percent. For the same two structural measures, time of day also emerged as a reliable predictor with an estimated diurnal volume decrease of, again, about 1 percent. Furthermore, we found weak predictive evidence for the number of steps taken on the previous day and testosterone levels. The results suggest a need to control for time-of-day effects in sMRI research. In particular, we recommend that researchers interested in assessing longitudinal change in the context of intervention studies or longitudinal panels make sure that, at each measurement occasion, (a) a given participant is measured at the same time of day; (b) participants overall are measured at about the same time of day. Furthermore, the potential effects of physical activity, including moderate amounts of aerobic exercise, and testosterone levels on MRI-based measures of brain structure deserve further investigation.
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