| 1. |
- Grill, Filip, 1989-
(författare)
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Dopamine and the affective-cognitive gradient in the human striatum studied with multimodal brain imaging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Both dopamine and the dopamine rich brain area, striatum, have been linked to behaviors related to incentives, motor action, and associative processing. Most of the cortex sends projections to the striatum, these connections have been described as a gradient organization representing a repertoire of functional behaviors. Although considerable research efforts have been made on the functions of dopamine, it is still unclear how and when it is released in the striatum in humans and what role it has for everyday behavior.The overarching aim of this thesis is to contribute to our understanding of the role of striatal dopamine release during human behaviors relating to incentive, motor, and associative processing. Using a combination of multimodal brain imaging (positron emission tomography and functional magnetic resonance imaging) as well as cognitive modelling this thesis investigates: how a reproducible striatal response to incentives can be divided into behaviorally relevant components relating to affective and cognitive processes, how striatal dopamine release during motor action represent several component processes of behavior, and also provides evidence that striatal dopamine is released during reward prediction errors in humans. The results are consistent with an affective-cognitive gradient in the striatum and suggest that dopamine release into the striatal gradient might facilitate the integration of component processes into complex representations of behavior. The results of this thesis are based on healthy young individuals, however, aberrant dopamine signaling is a hallmark of several psychiatric and neurological diseases making it crucial to further understand the healthy dopamine system.
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| 2. |
- Pedersen, Robin, 1989-
(författare)
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The architecture of the aging brain : functional reorganization, structural changes, and the role of dopamine receptors
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aging is associated with reorganization of functional brain architecture, potentially leading tocognitive decline in older age. However, the mechanisms responsible for alterations in functionalbrain architecture remain poorly understood. Using a combination of multimodal neuroimagingtechniques and advanced statistical analyses in four independent studies, this thesis aims tocontribute to our understanding of age-related alterations in functional brain architecture andcognitive decline. Study I demonstrated age-related decline in functional brain network segregationin a longitudinal setting. Age-related changes in network segregation were associated withconcomitant losses of white matter integrity and domain-general cognitive function. Study II testedthe hypothesis that older age and lower dopamine D1-receptor (D1DR) availability concomitantly arerelated to less segregated network structure in older age. The results supported the hypothesis,revealing that greater D1DR availability in older age is associated with a more youth-like functionalarchitecture and greater working memory performance compared to age-matched counterparts withless D1DR. Study III further assessed the relationship between D1DR organization and functionalarchitecture. Using a non-linear decomposition method, we demonstrate that the spatial coexpression and distribution of D1DRs are aligned with the principal organization of brain function.Individual differences in D1DR distribution were related to the degree of functional differentiationbetween unimodal and transmodal cortices. Study IV investigated age-related differences in thefunctional organization of the hippocampus, revealing three overlapping modes of organization. Amedial-to-anterior and posterior mode largely corresponded to macroscale cortical organization ofconnectivity, aligned with local D1DR topography. Older age was associated with less distinctorganization of cortico-hippocampal connectivity, and maintenance of youth-like hippocampalorganization in older age was related to superior episodic memory function. Collectively, this thesisoffers multiple lines of evidence for age-related alterations in functional brain organization,associations with white-matter integrity and cognitive function, in addition to a novel link betweenfunctional brain architecture and the D1DR system.
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| 3. |
- Rieckmann, Anna
(författare)
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Human aging, dopamine, and cognition : molecular and functional imaging of executive functions and implicit learning
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Age-related deficits are legion in task switching, updating of information in working memory (WM) and inhibiting irrelevant information, collectively referred to as executive functions. Executive functions are tightly coupled to the dopaminergic system, and marked dopamine (DA) losses are observed across adulthood and aging. Several human molecular imaging studies have sought confirmation for the hypothesis that age-related DA losses are associated with deficits in executive functions in older adults. Study I extends this line of research by investigating the association between caudate DA D1 receptor density and functional network connectivity in younger (20-30 years) and older adults (65-75 years) using positron emission tomography and functional magnetic resonance imaging (fMRI). In line with the notion that striatal DA is a critical modulator in cortico-striato-cortical pathways, caudate D1 receptor density was significantly associated with fronto-parietal connectivity in functional brain networks related to executive functioning, and there were marked age-related reductions in DA D1 binding potential. These results show that age-related losses of caudate D1 receptors may contribute to reduced functional-network integrity in older adults. Study II examined age differences in D1 receptor density in several striatal and cortical regions of interest. On average, D1 receptor densities were reduced by around 20 % for older compared to younger adults. Most interestingly, correlations between striatal and cortical receptor densities were reduced in older compared to younger adults, suggesting that dopaminergic losses in striatum and cortex occur relatively independently. Moreover, reduced correlations between striatal and cortical receptor densities were related to slower cognitive interference resolution in older adults. This pattern suggests that an imbalance in dopaminergic regulation between striatum and cortex may contribute to older adults’ deficits in executive functions. Implicit learning remains relatively spared in older adults despite strong associations to striatal functions and DA. This fact presents a paradox for the hypothesis that age-related DA losses mediate cognitive decline in aging. Study III and IV explore possible compensatory mechanisms, which may contribute to preserved implicit learning among older adults. Study III showed that increases in striatal fMRI activations during implicit sequence learning were accompanied by decreasing activation of the right medial temporal lobe (MTL) in younger adults. Older adults, however, relied on both striatum and right MTL during task performance. This pattern suggests that the MTL is not necessary for implicit learning in younger adults, but serves compensatory purposes in old age. Study IV used a dual-task design during fMRI acquisition in which a secondary task, designed to tax the MTL, was performed concurrent with an implicit sequence-learning task comparable to that used in Study III. Consistent with the interpretation of the data from Study III, the secondary task disrupted learning in older, but not younger adults. Moreover, differential effects of the secondary task on learning in younger and older adults were observed in activation patterns for right MTL. Collectively, the four studies provide novel insights into the mechanisms by which dopaminergic losses in aging contribute to deficits in executive functions, and suggest compensatory processes, which may account for the relative sparing of implicit learning in old age.
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