| 1. |
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| 2. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 3. |
- Korenblik, R., et al.
(författare)
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Dragon 1 Protocol Manuscript : Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy
- 2022
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Ingår i: Cardiovascular and Interventional Radiology. - : Springer. - 0174-1551 .- 1432-086X. ; 45, s. 1391-1398
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Tidskriftsartikel (refereegranskat)abstract
- Study Purpose The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. Methods The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. Results Not applicable. Conclusion DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR.
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| 4. |
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| 6. |
- Guitart-Masip, Marc, et al.
(författare)
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Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment
- 2014
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 231:5, s. 955-966
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Tidskriftsartikel (refereegranskat)abstract
- Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing. To investigate the role of dopamine and serotonin in the interaction between action and valence during learning. We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively. We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition. Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.
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| 7. |
- Johannesson, M, et al.
(författare)
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A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock
- 2009
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 19:1, s. 150-158
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Tidskriftsartikel (refereegranskat)abstract
- The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance.
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| 8. |
- Betts, Matthew J., et al.
(författare)
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Learning in anticipation of reward and punishment : perspectives across the human lifespan
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 96, s. 49-57
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Tidskriftsartikel (refereegranskat)abstract
- Learning to act to receive reward and to withhold to avoid punishment has been found to be easier than learning the opposite contingencies in young adults. To what extent this type of behavioral adaptation might develop during childhood and adolescence and differ during aging remains unclear. We therefore tested 247 healthy individuals across the human life span (7–80 years) with an orthogonalized valenced go/no-go learning task. Computational modeling revealed that peak performance in young adults was attributable to greater sensitivity to both reward and punishment. However, in children and adolescents, we observed an increased bias toward action but not reward sensitivity. By contrast, reduced learning in midlife and older adults was accompanied by decreased reward sensitivity and especially punishment sensitivity along with an age-related increase in the Pavlovian bias. These findings reveal distinct motivation-dependent learning capabilities across the human life span, which cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implications in lifelong education.
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| 9. |
- Adams, Rick A., et al.
(författare)
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Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans : A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models
- 2020
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:6, s. 3573-3589
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Tidskriftsartikel (refereegranskat)abstract
- Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [C-11]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D(2/3)Rs decreasing the variability of action selection in humans.
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| 10. |
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| 11. |
- Bach, Dominik R., et al.
(författare)
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Human Hippocampus Arbitrates Approach-Avoidance Conflict
- 2014
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 24:5, s. 541-547
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Tidskriftsartikel (refereegranskat)abstract
- Animal models of human anxiety often invoke a conflict between approach and avoidance [1, 2]. In these, a key behavioral assay comprises passive avoidance of potential threat and inhibition, both thought to be controlled by ventral hippocampus [2-6]. Efforts to translate these approaches to clinical contexts [7, 8] are hampered by the fact that it is not known whether humans manifest analogous approach-avoidance dispositions and, if so, whether they share a homologous neurobiological substrate [9]. Here, we developed a paradigm to investigate the role of human hippocampus in arbitrating an approach-avoidance conflict under varying levels of potential threat. Across four experiments, subjects showed analogous behavior by adapting both passive avoidance behavior and behavioral inhibition to threat level. Using functional magnetic resonance imaging (fMRI), we observe that threat level engages the anterior hippocampus, the human homolog of rodent ventral hippocampus [10]. Testing patients with selective hippocampal lesions, we demonstrate a causal role for the hippocampus with patients showing reduced passive avoidance behavior and inhibition across all threat levels. Our data provide the first human assay for approach-avoidance conflict akin to that of animal anxiety models. The findings bridge rodent and human research on passive avoidance and behavioral inhibition and furnish a framework for addressing the neuronal underpinnings of human anxiety disorders, where our data indicate a major role for the hippocampus.
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| 12. |
- Chowdhury, Rumana, et al.
(författare)
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Dopamine restores reward prediction errors in old age
- 2013
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 16:5, s. 648-653
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Tidskriftsartikel (refereegranskat)abstract
- Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA.
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| 13. |
- Cunliffe, Michael, et al.
(författare)
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Sea surface microlayers : A unified physicochemical and biological perspective of the air-ocean interface
- 2013
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Ingår i: Progress in Oceanography. - : Elsevier BV. - 0079-6611 .- 1873-4472. ; 109, s. 104-116
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Forskningsöversikt (refereegranskat)abstract
- The sea surface microlayer (SML) covers more than 70% of the Earth's surface and is the boundary layer interface between the ocean and the atmosphere. This important biogeochemical and ecological system is critical to a diverse range of Earth system processes, including the synthesis, transformation and cycling of organic material, and the air-sea exchange of gases, particles and aerosols. In this review we discuss the SML paradigm, taking into account physicochemical and biological characteristics that define SML structure and function. These include enrichments in biogenic molecules such as carbohydrates, lipids and proteinaceous material that contribute to organic carbon cycling, distinct microbial assemblages that participate in air-sea gas exchange, the generation of climate-active aerosols and the accumulation of anthropogenic pollutants with potentially serious implications for the health of the ocean. Characteristically large physical, chemical and biological gradients thus separate the SML from the underlying water and the available evidence implies that the SML retains its integrity over wide ranging environmental conditions. In support of this we present previously unpublished time series data on bacterioneuston composition and SML surfactant activity immediately following physical SML disruption; these imply timescales of the order of minutes for the reestablishment of the SML following disruption. A progressive approach to understanding the SML and hence its role in global biogeochemistry can only be achieved by considering as an integrated whole, all the key components of this complex environment.
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| 14. |
- de Boer, Lieke, et al.
(författare)
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Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:1, s. 261-270
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Tidskriftsartikel (refereegranskat)abstract
- Learning to act to obtain reward and inhibit to avoid punishment is easier compared with learning the opposite contingencies. This coupling of action and valence is often thought of as a Pavlovian bias, although recent research has shown it may also emerge through instrumental mechanisms. We measured this learning bias with a rewarded go/no-go task in 60 adults of different ages. Using computational modeling, we characterized the bias as being instrumental. To assess the role of endogenous dopamine (DA) in the expression of this bias, we quantified DA D1 receptor availability using positron emission tomography (PET) with the radioligand [11C]SCH23390. Using principal-component analysis on the binding potentials in a number of cortical and striatal regions of interest, we demonstrated that cortical, dorsal striatal, and ventral striatal areas provide independent sources of variance in DA D1 receptor availability. Interindividual variation in the dorsal striatal component was related to the strength of the instrumental bias during learning. These data suggest at least three anatomical sources of variance in DA D1 receptor availability separable using PET in humans, and we provide evidence that human dorsal striatal DA D1 receptors are involved in the modulation of instrumental learning biases.
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| 15. |
- Economides, Marcos, et al.
(författare)
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Anterior Cingulate Cortex Instigates Adaptive Switches in Choice by Integrating Immediate and Delayed Components of Value in Ventromedial Prefrontal Cortex
- 2014
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 34:9, s. 3340-3349
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Tidskriftsartikel (refereegranskat)abstract
- Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action.
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| 16. |
- Economides, M., et al.
(författare)
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Arbitration between controlled and impulsive choices
- 2015
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 109, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- The impulse to act for immediate reward often conflicts with more deliberate evaluations that support long-term benefit. The neural architecture that negotiates this conflict remains unclear. One account proposes a single neural circuit that evaluates both immediate and delayed outcomes, while another outlines separate impulsive and patient systems that compete for behavioral control. Here we designed a task in which a complex payout structure divorces the immediate value of acting from the overall long-term value, within the same outcome modality. Using model-based fMRI in humans, we demonstrate separate neural representations of immediate and long-term values, with the former tracked in the anterior caudate (AC) and the latter in the ventromedial prefrontal cortex (vmPFC). Crucially, when subjects' choices were compatible with long-run consequences, value signals in AC were down-weighted and those in vmPFC were enhanced, while the opposite occurred when choice was impulsive. Thus, our data implicate a trade-off in value representation between AC and vmPFC as underlying controlled versus impulsive choice.
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| 17. |
- Ereira, Sam, et al.
(författare)
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Overcoming Pavlovian bias in semantic space
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Action is invigorated in the presence of reward-predicting stimuli and inhibited in the presence of punishment-predicting stimuli. Although valuable as a heuristic, this Pavlovian bias can also lead to maladaptive behaviour and is implicated in addiction. Here we explore whether Pavlovian bias can be overcome through training. Across five experiments, we find that Pavlovian bias is resistant to unlearning under most task configurations. However, we demonstrate that when subjects engage in instrumental learning in a verbal semantic space, as opposed to a motoric space, not only do they exhibit the typical Pavlovian bias, but this Pavlovian bias diminishes with training. Our results suggest that learning within the semantic space is necessary, but not sufficient, for subjects to unlearn their Pavlovian bias, and that other task features, such as gamification and spaced stimulus presentation may also be necessary. In summary, we show that Pavlovian bias, whilst robust, is susceptible to change with experience, but only under specific environmental conditions.
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| 18. |
- Hird, Emily J., et al.
(författare)
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Dopamine and reward-related vigor in younger and older adults
- 2022
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 118, s. 34-43
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Tidskriftsartikel (refereegranskat)abstract
- Vigor reflects how motivated people are to respond to stimuli. We previously showed that, on average, humans are more vigorous when a higher rate of reward is available, and that this relationship is modulated by the dopamine precursor levodopa. Dopamine signaling and probabilistic reward learning deteriorate across the adult life span, and thus, the relationship between vigor and reward may also change in aging. We tested this assertion and assessed whether it correlates with D1 dopamine receptor availability, measured using Positron Emission Tomography. We registered response times of 30 older and 30 younger participants during an oddball discrimination task where rewards varied systematically between trials. The average reward rate had a similar impact on vigor in both age groups. There was a weak positive association between ventral striatal dopamine receptor availability and the effect of average reward rate on response time. Overall, the effect of reward on response vigor was similar in younger and older adults, and weakly correlated with dopamine D1 receptor availability.
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| 19. |
- Katsaros, Gregory, et al.
(författare)
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A service framework for energy-aware monitoring and VM management in Clouds
- 2013
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Ingår i: Future generations computer systems. - : Elsevier. - 0167-739X .- 1872-7115. ; 29:8, s. 2077-2091
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Tidskriftsartikel (refereegranskat)abstract
- The monitoring of QoS parameters in Services Computing as well as in Clouds has been a functionality provided by all contemporary systems. As the optimization of energy consumption becomes a major concern for system designers and administrators, it can be considered as another QoS metric to be monitored. In this paper, we present a service framework that allows us to monitor the energy consumption of a Cloud infrastructure, calculate its energy efficiency, and evaluate the gathered data in order to put in place an effective virtual machine (VM) management. In that context, a simulation scenario of an eco-driven VM placement policy resulted in a 14% improvement of the infrastructure's energy efficiency. In total, the proposed approaches and implementations have been validated against a testbed, producing very promising results regarding the prospect of energy efficiency as an important quality factor in Clouds. (C) 2012 Elsevier B.V. All rights reserved.
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| 20. |
- Koster, Raphael, et al.
(författare)
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Basal Ganglia Activity Mirrors a Benefit of Action and Reward on Long-Lasting Event Memory
- 2015
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 25:12, s. 4908-4917
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Tidskriftsartikel (refereegranskat)abstract
- The expectation of reward is known to enhance a consolidation of long-term memory for events. We tested whether this effect is driven by positive valence or action requirements tied to expected reward. Using a functional magnetic resonance imaging (fMRI) paradigm in young adults, novel images predicted gain or loss outcomes, which in turn were either obtained or avoided by action or inaction. After 24 h, memory for these images reflected a benefit of action as well as a congruence of action requirements and valence, namely, action for reward and inaction for avoidance. fMRI responses in the hippocampus, a region known to be critical for long-term memory function, reflected the anticipation of inaction. In contrast, activity in the putamen mirrored the congruence of action requirement and valence, whereas other basal ganglia regions mirrored overall action benefits on long-lasting memory. The findings indicate a novel type of functional division between the hippocampus and the basal ganglia in the motivational regulation of long-term memory consolidation, which favors remembering events that are worth acting for.
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| 21. |
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| 22. |
- Moutoussis, Michael, et al.
(författare)
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Neural activity and fundamental learning, motivated by monetary loss and reward, are intact in mild to moderate major depressive disorder
- 2018
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Reduced motivation is an important symptom of major depression, thought to impair recovery by reducing opportunities for rewarding experiences. We characterized motivation for monetary outcomes in depressed outpatients (N = 39, 22 female) and controls (N = 22, 11 female) in terms of their effectiveness in seeking rewards and avoiding losses. We assessed motivational function during learning of associations between stimuli and actions, as well as when learning was complete. We compared the activity within neural circuits underpinning these behaviors between depressed patients and controls. Methods We used a Go/No-Go task that assessed subjects' abilities in learning to emit or withhold actions to obtain monetary rewards or avoid losses. We derived motivation-relevant parameters of behavior (learning rate, Pavlovian bias, and motivational influence of gains and losses). After learning, participants performed the task during functional magnetic resonance imaging (fMRI). We compared neural activation during anticipation of action emission vs. action inhibition, and for actions performed to obtain rewards compared to actions that avoid losses. Results Depressed patients showed a similar Pavlovian bias to controls and were equivalent in terms of withholding action to gain rewards and emitting action to avoid losses, behaviors that conflict with well-described Pavlovian tendencies to approach rewards and avoid losses. Patients were not impaired in overall performance or learning and showed no abnormal neural responses, for example in bilateral midbrain or striatum. We conclude that basic mechanisms subserving motivated learning are thus intact in moderate depression. Implications Therapeutically, the intact mechanisms identified here suggest that learning-based interventions may be particularly effective in encouraging recovery. Etiologically, our results suggest that the severe motivational deficits clinically observed in depression are likely to have complex origins, possibly related to an impairment in the representation of future states necessary for long-term planning.
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| 23. |
- Perosa, Valentina, et al.
(författare)
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The Role of the Striatum in Learning to Orthogonalize CD Action and Valence : A Combined PET and 7 T MRI Aging Study
- 2020
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:5, s. 3340-3351
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Tidskriftsartikel (refereegranskat)abstract
- Pavlovian biases influence instrumental learning by coupling reward seeking with action invigoration and punishment avoidance with action suppression. Using a probabilistic go/no-go task designed to orthogonalize action (go/no-go) and valence (reward/punishment), recent studies have shown that the interaction between the two is dependent on the striatum and its key neuromodulator dopamine. Using this task, we sought to identify how structural and neuromodulatory age-related differences in the striatum may influence Pavlovian biases and instrumental learning in 25 young and 31 older adults. Computational modeling revealed a significant age-related reduction in reward and punishment sensitivity and marked (albeit not significant) reduction in learning rate and lapse rate (irreducible noise). Voxel-based morphometry analysis using 7 Tesla MRI images showed that individual differences in learning rate in older adults were related to the volume of the caudate nucleus. In contrast, dopamine synthesis capacity in the dorsal striatum, assessed using [F-18]-DOPA positron emission tomography in 22 of these older adults, was not associated with learning performance and did not moderate the relationship between caudate volume and learning rate. This multiparametric approach suggests that age-related differences in striatal volume may influence learning proficiency in old age.
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