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Pedersen, R., Johansson, J., Nordin, K., Rieckmann, A., Wåhlin, A., Nyberg, L., . . . Salami, A. (2024). Dopamine D1-receptor organization contributes to functional brain architecture. Journal of Neuroscience, 44(11), Article ID e0621232024.
Open this publication in new window or tab >>Dopamine D1-receptor organization contributes to functional brain architecture
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2024 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 44, no 11, article id e0621232024Article in journal (Refereed) Published
Abstract [en]

Recent work has recognized a gradient-like organization in cortical function, spanning from primary sensory to transmodal cortices. It has been suggested that this axis is aligned with regional differences in neurotransmitter expression. Given the abundance of dopamine D1-receptors (D1DR), and its importance for modulation and neural gain, we tested the hypothesis that D1DR organization is aligned with functional architecture, and that inter-regional relationships in D1DR co-expression modulate functional cross talk. Using the world's largest dopamine D1DR-PET and MRI database (N = 180%, 50% female), we demonstrate that D1DR organization follows a unimodal–transmodal hierarchy, expressing a high spatial correspondence to the principal gradient of functional connectivity. We also demonstrate that individual differences in D1DR density between unimodal and transmodal regions are associated with functional differentiation of the apices in the cortical hierarchy. Finally, we show that spatial co-expression of D1DR primarily modulates couplings within, but not between, functional networks. Together, our results show that D1DR co-expression provides a biomolecular layer to the functional organization of the brain.

Place, publisher, year, edition, pages
Society for Neuroscience, 2024
Keywords
architecture, dopamine, functional connectivity, gradients, organization
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-222641 (URN)10.1523/JNEUROSCI.0621-23.2024 (DOI)38302439 (PubMedID)2-s2.0-85187783583 (Scopus ID)
Available from: 2024-04-19 Created: 2024-04-19 Last updated: 2024-04-19Bibliographically approved
Grill, F., Guitart-Masip, M., Johansson, J., Stiernman, L., Axelsson, J., Nyberg, L. & Rieckmann, A. (2024). Dopamine release in human associative striatum during reversal learning. Nature Communications, 15(1), Article ID 59.
Open this publication in new window or tab >>Dopamine release in human associative striatum during reversal learning
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 59Article in journal (Refereed) Published
Abstract [en]

The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-219310 (URN)10.1038/s41467-023-44358-w (DOI)38167691 (PubMedID)2-s2.0-85181231291 (Scopus ID)
Available from: 2024-01-12 Created: 2024-01-12 Last updated: 2024-01-12Bibliographically approved
Özalay, Ö., Mediavilla, T., Giacobbo, B. L., Pedersen, R., Marcellino, D., Orädd, G., . . . Sultan, F. (2024). Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging. Communications Biology, 7(1), Article ID 210.
Open this publication in new window or tab >>Longitudinal monitoring of the mouse brain reveals heterogenous network trajectories during aging
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2024 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 7, no 1, article id 210Article in journal (Refereed) Published
Abstract [en]

The human aging brain is characterized by changes in network efficiency that are currently best captured through longitudinal resting-state functional MRI (rs-fMRI). These studies however are challenging due to the long human lifespan. Here we show that the mouse animal model with a much shorter lifespan allows us to follow the functional network organization over most of the animal’s adult lifetime. We used a longitudinal study of the functional connectivity of different brain regions with rs-fMRI under anesthesia. Our analysis uncovers network modules similar to those reported in younger mice and in humans (i.e., prefrontal/default mode network (DMN), somatomotor and somatosensory networks). Statistical analysis reveals different patterns of network reorganization during aging. Female mice showed a pattern akin to human aging, with de-differentiation of the connectome, mainly due to increases in connectivity of the prefrontal/DMN cortical networks to other modules. Our male cohorts revealed heterogenous aging patterns with only one group confirming the de- differentiation, while the majority showed an increase in connectivity of the somatomotor cortex to the Nucleus accumbens. In summary, in line with human work, our analysis in mice supports the concept of de-differentiation in the aging mammalian brain and reveals additional trajectories in aging mice networks.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Neurosciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-221665 (URN)10.1038/s42003-024-05873-8 (DOI)38378942 (PubMedID)2-s2.0-85185453116 (Scopus ID)
Funder
The Kempe Foundations, JCK-1922.2
Available from: 2024-03-01 Created: 2024-03-01 Last updated: 2024-03-01Bibliographically approved
Johansson, J., Nordin, K., Pedersen, R., Karalija, N., Papenberg, G., Andersson, M., . . . Salami, A. (2023). Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan. Cell Reports, 42(9), Article ID 113107.
Open this publication in new window or tab >>Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan
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2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 9, article id 113107Article in journal (Refereed) Published
Abstract [en]

Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.

Keywords
aging, cognition, CP: Neuroscience, dopamine D1, functional connectivity, neuromodulation, protracted development
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-214414 (URN)10.1016/j.celrep.2023.113107 (DOI)2-s2.0-85169884676 (Scopus ID)
Funder
Swedish Research Council, 2016-01936Knut and Alice Wallenberg FoundationRiksbankens Jubileumsfond
Available from: 2023-09-18 Created: 2023-09-18 Last updated: 2024-01-17Bibliographically approved
Young, P., Appel, L., Tolf, A., Kosmidis, S., Burman, J., Rieckmann, A., . . . Lubberink, M. (2023). Image-derived input functions from dynamic 15O–water PET scans using penalised reconstruction. EJNMMI Physics, 10(1), Article ID 15.
Open this publication in new window or tab >>Image-derived input functions from dynamic 15O–water PET scans using penalised reconstruction
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2023 (English)In: EJNMMI Physics, E-ISSN 2197-7364, Vol. 10, no 1, article id 15Article in journal (Refereed) Published
Abstract [en]

Background: Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide.

Results: IDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%.

Conclusion: Our results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
15O–water PET, Cerebral blood flow, Image-derived input function, Partial volume correction, PET
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:umu:diva-205929 (URN)10.1186/s40658-023-00535-w (DOI)000945364200001 ()36881266 (PubMedID)2-s2.0-85149907346 (Scopus ID)
Available from: 2023-03-27 Created: 2023-03-27 Last updated: 2023-09-05Bibliographically approved
Panes Lundmark, V., Josefsson, M. & Rieckmann, A. (2023). Predictors of loneliness onset and maintenance in European older adults during the COVID-19 pandemic. Frontiers in Psychology, 14, Article ID 1172552.
Open this publication in new window or tab >>Predictors of loneliness onset and maintenance in European older adults during the COVID-19 pandemic
2023 (English)In: Frontiers in Psychology, E-ISSN 1664-1078, Vol. 14, article id 1172552Article in journal (Refereed) Published
Abstract [en]

Objectives: Loneliness is a major public health concern. Duration of loneliness is associated with severity of health outcomes, and further research is needed to direct interventions and social policy. This study aimed to identify predictors of the onset vs. the maintenance of loneliness in older adults before and during the pandemic using longitudinal data from the Survey of Health, Age, and Retirement in Europe (SHARE).

Methods: Groupings of persistent, situational, and no loneliness were based on self-reports from an ordinary pre-pandemic SHARE wave and a peri-pandemic telephone interview. Predictors were identified and compared in three hierarchical binary regression analyses, with independent variables added in blocks of geographic region, demographics, pre-pandemic social network, pre-pandemic health, pandemic-related individual, and country level variables.

Results: Self-reported loneliness levels for the persistent, situational, and no loneliness groups were stable and distinct through 7 years preceding the pre-pandemic baseline measure. Shared predictors were chronic diseases, female sex, depression, and no cohabitant partner. Persistent loneliness was uniquely predicted by low network satisfaction (OR: 2.04), functional limitations (OR: 1.40), and a longer country-level isolation period for older adults (OR: 1.24).

Conclusion: Interventions may target persons with depression, functional limitations, chronic health issues, and no cohabitant partner. The added burden of the length of isolation on those who are already lonely should be taken into account when employing social policies that target older adults. Further research should distinguish between situational and persistent loneliness, and seek to identify predictors of chronic loneliness onset.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
chronic loneliness, COVID-19, loneliness, longitudinal, pandemic, persistent loneliness, predictors, transient loneliness
National Category
Applied Psychology Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-211163 (URN)10.3389/fpsyg.2023.1172552 (DOI)001008488100001 ()37333579 (PubMedID)2-s2.0-85162181573 (Scopus ID)
Funder
EU, Horizon 2020, SHARE-COVID-19: GA No. 101015924EU, Horizon 2020, SHARE-DEV3: GA No. 676536EU, Horizon 2020, SHARE-COHESION: GA No. 870628EU, Horizon 2020, SERISS: GA No. 654221EU, Horizon 2020, SSHOC: GA No. 823782EU, FP7, Seventh Framework Programme, SHARE-PREP: GA No. 211909EU, FP7, Seventh Framework Programme, SHARE-LEAP: GA No. 227822EU, FP7, Seventh Framework Programme, SHARE M4: GA No. 261982EU, FP7, Seventh Framework Programme, DASISH: GA No. 283646EU Sixth Framework Programme for Research, SHARE-I3: RII-CT-2006-062193EU Sixth Framework Programme for Research, COMPARE: CIT5-CT-2005-028857EU Sixth Framework Programme for Research, SHARELIFE: CIT4-CT-2006-028812European Commission, QLK6-CT-2001-00360
Available from: 2023-07-04 Created: 2023-07-04 Last updated: 2023-07-04Bibliographically approved
Godbersen, G. M., Klug, S., Wadsak, W., Pichler, V., Raitanen, J., Rieckmann, A., . . . Hahn, A. (2023). Task-evoked metabolic demands of the posteromedial default mode network are shaped by dorsal attention and frontoparietal control networks. eLIFE, 12, Article ID e84683.
Open this publication in new window or tab >>Task-evoked metabolic demands of the posteromedial default mode network are shaped by dorsal attention and frontoparietal control networks
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2023 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id e84683Article in journal (Refereed) Published
Abstract [en]

External tasks evoke characteristic fMRI BOLD signal deactivations in the default mode network (DMN). However, for the corresponding metabolic glucose demands both decreases and increases have been reported. To resolve this discrepancy, functional PET/MRI data from 50 healthy subjects performing Tetris were combined with previously published data sets of working memory, visual and motor stimulation. We show that the glucose metabolism of the posteromedial DMN is dependent on the metabolic demands of the correspondingly engaged task-positive networks. Specifically, the dorsal attention and frontoparietal network shape the glucose metabolism of the posteromedial DMN in opposing directions. While tasks that mainly require an external focus of attention lead to a consistent downregulation of both metabolism and the BOLD signal in the posteromedial DMN, cognitive control during working memory requires a metabolically expensive BOLD suppression. This indicates that two types of BOLD deactivations with different oxygen-to-glucose index may occur in this region. We further speculate that consistent downregulation of the two signals is mediated by decreased glutamate signaling, while divergence may be subject to active GABAergic inhibition. The results demonstrate that the DMN relates to cognitive processing in a flexible manner and does not always act as a cohesive task-negative network in isolation.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd, 2023
Keywords
BOLD signal, deactivation, default mode network, functional PET, glucose metabolism, human, neuroscience
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-209558 (URN)10.7554/eLife.84683 (DOI)37226880 (PubMedID)2-s2.0-85160875279 (Scopus ID)
Available from: 2023-06-12 Created: 2023-06-12 Last updated: 2023-06-12Bibliographically approved
Stiernman, L., Grill, F., McNulty, C., Bahrd, P., Panes Lundmark, V., Axelsson, J., . . . Rieckmann, A. (2023). Widespread fMRI BOLD signal overactivations during cognitive control in older adults are not matched by corresponding increases in fPET glucose metabolism. Journal of Neuroscience, 43(14), 2527-2536
Open this publication in new window or tab >>Widespread fMRI BOLD signal overactivations during cognitive control in older adults are not matched by corresponding increases in fPET glucose metabolism
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2023 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 43, no 14, p. 2527-2536Article in journal (Refereed) Published
Abstract [en]

A common observation in fMRI studies using the BOLD signal is that older adults, compared with young adults, show overactivations, particularly during less demanding tasks. The neuronal underpinnings of such overactivations are not known, but a dominant view is that they are compensatory in nature and involve recruitment of additional neural resources. We scanned 23 young (20-37 years) and 34 older (65-86 years) healthy human adults of both sexes with hybrid positron emission tomography/MRI. The radioligand [18F]fluoro-deoxyglucose was used to assess dynamic changes in glucose metabolism as a marker of task-dependent synaptic activity, along with simultaneous fMRI BOLD imaging. Participants performed two verbal working memory (WM) tasks: one involving maintenance (easy) and one requiring manipulation (difficult) of information in WM. Converging activations to the WM tasks versus rest were observed for both imaging modalities and age groups in attentional, control, and sensorimotor networks. Upregulation of activity to WM-demand, comparing the more difficult to the easier task, also converged between both modalities and age groups. For regions in which older adults showed task-dependent BOLD overactivations compared with the young adults, no corresponding increases in glucose metabolism were found. To conclude, findings from the current study show that task-induced changes in the BOLD signal and synaptic activity as measured by glucose metabolism generally converge, but overactivations observed with fMRI in older adults are not coupled with increased synaptic activity, which suggests that these overactivations are not neuronal in origin.

Place, publisher, year, edition, pages
Society for Neuroscience, 2023
Keywords
aging, fMRI, glucose metabolism, overactivation, PET, working memory
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-206761 (URN)10.1523/JNEUROSCI.1331-22.2023 (DOI)000976532300008 ()36868855 (PubMedID)2-s2.0-85152165890 (Scopus ID)
Funder
EU, European Research Council, ERC-STG-716065EU, Horizon 2020Swedish Research Council, 2016-01936Knut and Alice Wallenberg FoundationRiksbankens Jubileumsfond, P20-0515
Available from: 2023-05-02 Created: 2023-05-02 Last updated: 2023-09-05Bibliographically approved
Giacobbo, B., Özalay, Ö., Mediavilla, T., Ericsson, M., Axelsson, J., Rieckmann, A., . . . Marcellino, D. (2022). The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice. Frontiers in Aging Neuroscience, 14, Article ID 795132.
Open this publication in new window or tab >>The Aged Striatum: Evidence of Molecular and Structural Changes Using a Longitudinal Multimodal Approach in Mice
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2022 (English)In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 14, article id 795132Article in journal (Refereed) Published
Abstract [en]

To study the aging human brain requires significant resources and time. Thus, mice models of aging can provide insight into changes in brain biological functions at a fraction of the time when compared to humans. This study aims to explore changes in dopamine D1 and D2 receptor availability and of gray matter density in striatum during aging in mice and to evaluate whether longitudinal imaging in mice may serve as a model for normal brain aging to complement cross-sectional research in humans. Mice underwent repeated structural magnetic resonance imaging (sMRI), and [11C]Raclopride and [11C]SCH23390 positron emission tomography (PET) was performed on a subset of aging mice. PET and sMRI data were analyzed by binding potential (BP ND ), voxel- and tensor-based morphometry (VBM and TBM, respectively). Longitudinal PET revealed a significant reduction in striatal BP ND for D2 receptors over time, whereas no significant change was found for D1 receptors. sMRI indicated a significant increase in modulated gray matter density (mGMD) over time in striatum, with limited clusters showing decreased mGMD. Mouse [11C]Raclopride data is compatible with previous reports in human cross-sectional studies, suggesting that a natural loss of dopaminergic D2 receptors in striatum can be assessed in mice, reflecting estimates from humans. No changes in D1 were found, which may be attributed to altered [11C]SCH23390 kinetics in anesthetized mice, suggesting that this tracer is not yet able to replicate human findings. sMRI revealed a significant increase in mGMD. Although contrary to expectations, this increase in modulated GM density may be attributed to an age-related increase in non-neuronal cells.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2022
Keywords
PET, VBM, aging, dopamine, senescence, structural MRI
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-193466 (URN)10.3389/fnagi.2022.795132 (DOI)000751826100001 ()35140600 (PubMedID)2-s2.0-85124354218 (Scopus ID)
Available from: 2022-04-04 Created: 2022-04-04 Last updated: 2023-05-04Bibliographically approved
Andersson, S., Josefsson, M., Stiernman, L. J. & Rieckmann, A. (2021). Cognitive decline in Parkinson’s disease: a subgroup of extreme decliners revealed by a data-driven analysis of longitudinal progression. Frontiers in Psychology, 12, Article ID 729755.
Open this publication in new window or tab >>Cognitive decline in Parkinson’s disease: a subgroup of extreme decliners revealed by a data-driven analysis of longitudinal progression
2021 (English)In: Frontiers in Psychology, E-ISSN 1664-1078, Vol. 12, article id 729755Article in journal (Refereed) Published
Abstract [en]

Cognitive impairment is an important symptom of Parkinson’s disease (PD) and predicting future cognitive decline is crucial for clinical practice. Here, we aim to identify latent sub-groups of longitudinal trajectories of cognitive change in PD patients, and explore predictors of differences in cognitive change. Longitudinal cognitive performance data from 349 newly diagnosed PD patients and 145 healthy controls from the Parkinson Progression Marker Initiative were modeled using a multivariate latent class linear mixed model. Resultant latent classes were compared on a number of baseline demographics, and clinical variables, as well as cerebrospinal fluid (CSF) biomarkers and striatal dopamine transporter (DAT) density markers of neuropathology. Trajectories of cognitive change in PD were best described by two latent classes. A large subgroup (90%), which showed a subtle impairment in cognitive performance compared to controls but remained stable over the course of the study, and a small subgroup (10%) which rapidly declined in all cognitive performance measures. Rapid decliners did not differ significantly from the larger group in terms of disease duration, severity or motor symptoms at baseline. However, rapid decliners had lower CSF amyloidß42 levels, a higher prevalence of sleep disorder and pronounced loss of caudate DAT density at baseline. These data suggest the existence of a distinct minority sub-type of PD in which rapid cognitive change in PD can occur uncoupled from motor symptoms or disease severity, likely reflecting early pathological change that extends from motor areas of the striatum into associative compartments and cortex.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2021
Keywords
cognitive decline, Cluster analysis, Longitudinal, Parkinson's disease, subtypes
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-186768 (URN)10.3389/fpsyg.2021.729755 (DOI)000698637400001 ()34566817 (PubMedID)2-s2.0-85115623705 (Scopus ID)
Funder
EU, Horizon 2020, 716065
Available from: 2021-08-20 Created: 2021-08-20 Last updated: 2023-03-24Bibliographically approved
Projects
Hybrid PET-MR imaging of dopamine release in humans: A potential biomarker for schizophrenia? [2015-03080_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5389-1578

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