Publications by authors named "Micael Andersson"

40 Publications

When functional blurring becomes deleterious: Reduced system segregation is associated with less white matter integrity and cognitive decline in aging.

Neuroimage 2021 Nov 3;242:118449. Epub 2021 Aug 3.

Department of Integrative Medical Biology, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden; Aging Research Center (ARC), Karolinska Institutet and Stockholm University, Stockholm, Sweden.

Healthy aging is accompanied by progressive decline in cognitive performance and concomitant changes in brain structure and functional architecture. Age-accompanied alterations in brain function have been characterized on a network level as weaker functional connections within brain networks along with stronger interactions between networks. This phenomenon has been described as age-related differences in functional network segregation. It has been suggested that functional networks related to associative processes are particularly sensitive to age-related deterioration in segregation, possibly related to cognitive decline in aging. However, there have been only a few longitudinal studies with inconclusive results. Here, we used a large longitudinal sample of 284 participants between 25 to 80 years of age at baseline, with cognitive and neuroimaging data collected at up to three time points over a 10-year period. We investigated age-related changes in functional segregation among two large-scale systems comprising associative and sensorimotor-related resting-state networks. We found that functional segregation of associative systems declines in aging with exacerbated deterioration from the late fifties. Changes in associative segregation were positively associated with changes in global cognitive ability, suggesting that decreased segregation has negative consequences for domain-general cognitive functions. Age-related changes in system segregation were partly accounted for by changes in white matter integrity, but white matter integrity only weakly influenced the association between segregation and cognition. Together, these novel findings suggest a cascade where reduced white-matter integrity leads to less distinctive functional systems which in turn contributes to cognitive decline in aging.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118449DOI Listing
November 2021

Sex differences in dopamine integrity and brain structure among healthy older adults: Relationships to episodic memory.

Neurobiol Aging 2021 09 2;105:272-279. Epub 2021 May 2.

Aging Research Center, Karolinska Institute & Stockholm University, Stockholm, Sweden.

Normal brain aging is a multidimensional process that includes deterioration in various brain structures and functions, with large heterogeneity in patterns and rates of decline. Sex differences have been reported for various cognitive and brain parameters, but little is known in relation to neuromodulatory aspects of brain aging. We examined sex differences in dopamine D2-receptor (D2DR) availability in relation to episodic memory, but also, grey-matter volumes, white-matter lesions, and cerebral perfusion in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging study. Women had higher D2DR availability in midbrain and left caudate and putamen, as well as superior episodic memory performance. Controlling for left caudate D2DR availability attenuated sex differences in memory performance. In men, lower left caudate D2DR levels were associated with lower cortical perfusion and higher burden of white-matter lesions, as well as with episodic memory performance. However, sex was not a significant moderator of the reported links to D2DR levels. Our findings suggest that sex differences in multiple associations among DA receptor availability, vascular factors, and structural connectivity contribute to sex differences in episodic memory. Future longitudinal studies need to corroborate these patterns by lead-lag associations. This manuscript is part of the Special Issue entitled 'Cognitive Neuroscience of Healthy and Pathological Aging' edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.022DOI Listing
September 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes.

PLoS One 2021 19;16(3):e0247753. Epub 2021 Mar 19.

Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden.

How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247753PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978337PMC
September 2021

Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability.

Cereb Cortex 2021 06;31(7):3435-3450

Umeå Center for Functional Brain Imaging, Umeå University, S-90187 Umeå, Sweden.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64-68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior-temporal/posterior-medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior-posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.
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http://dx.doi.org/10.1093/cercor/bhab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196260PMC
June 2021

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 17. Epub 2021 Feb 17.

Laboratory of Psychiatric Neuroimaging, Departamento e Instituto de Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.
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http://dx.doi.org/10.1002/hbm.25364DOI Listing
February 2021

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years.

Hum Brain Mapp 2021 Feb 11. Epub 2021 Feb 11.

Department of Psychology, Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.
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http://dx.doi.org/10.1002/hbm.25320DOI Listing
February 2021

Retrieval practice facilitates learning by strengthening processing in both the anterior and posterior hippocampus.

Brain Behav 2021 01 22;11(1):e01909. Epub 2020 Oct 22.

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umea, Sweden.

Introduction And Methods: A large number of behavioral studies show that retrieval practice is a powerful way of strengthening learning of new information. Repeated retrieval might support long-term retention in a quantitative sense by inducing stronger episodic representations or in a qualitative sense by contributing to the formation of more gist-like representations. Here we used fMRI to examine the brain bases related to the learning effects following retrieval practice and provide imaging support for both views by showing increased activation of anterior and posterior hippocampus regions during a delayed memory test.

Results: Brain activity in the posterior hippocampus increased linearly as a function of number of successful retrievals during initial learning, whereas anterior hippocampus activity was restricted to items retrieved many but not few times during the learning phase.

Conclusion: Taken together, these findings indicate that retrieval practice strengthens subsequent retention via "dual action" in the anterior and posterior hippocampus, possibly reflecting coding of individual experiences as well as integration and generalization across multiple experiences. Our findings are of educational significance by providing insight into the brain bases of a learning method of applied relevance.
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http://dx.doi.org/10.1002/brb3.1909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821628PMC
January 2021

Forecasting memory function in aging: pattern-completion ability and hippocampal activity relate to visuospatial functioning over 25 years.

Neurobiol Aging 2020 10 12;94:217-226. Epub 2020 Jun 12.

Department of Radiation Sciences, Umeå University, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.

Heterogeneity in episodic memory functioning in aging was assessed with a pattern-completion functional magnetic resonance imaging task that required reactivation of well-consolidated face-name memory traces from fragmented (partial) or morphed (noisy) face cues. About half of the examined individuals (N = 101) showed impaired (chance) performance on fragmented faces despite intact performance on complete and morphed faces, and they did not show a pattern-completion response in hippocampus or the examined subfields (CA1, CA23, DGCA4). This apparent pattern-completion deficit could not be explained by differential hippocampal atrophy. Instead, the impaired group displayed lower cortical volumes, accelerated reduction in mini-mental state examination scores, and lower general cognitive function as defined by longitudinal measures of visuospatial functioning and speed-of-processing. In the full sample, inter-individual differences in visuospatial functioning predicted performance on fragmented faces and hippocampal CA23 subfield activity over 25 years. These findings suggest that visuospatial functioning in middle age can forecast pattern-completion deficits in aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.005DOI Listing
October 2020

Elevated plasma neurofilament light in aging reflects brain white-matter alterations but does not predict cognitive decline or Alzheimer's disease.

Alzheimers Dement (Amst) 2020 23;12(1):e12050. Epub 2020 Jun 23.

Department of Clinical Sciences Umeå University Umeå Sweden.

Introduction: We investigated neurofilament light (NFL) accumulation in normal aging as well as in preclinical and clinical Alzheimer's disease (AD) and assessed individual differences in NFL load in relation to cognition and brain white-matter integrity.

Methods: We analyzed longitudinal data covering 30 years (1988-2017). Cognitive testing was done up to six times. Plasma NFL was quantified for controls and 142 cases who developed AD over time, and longitudinal changes in NFL were quantified for 100 individuals with three brain-imaging sessions.

Results: Longitudinal analyses revealed age-related NFL increases with marked variability. AD cases had elevated NFL levels, while no significant group differences were seen in the preclinical phase. Variability in NFL levels showed non-significant correlations with cognition but was associated with brain white matter.

Discussion: Our findings suggest that elevated blood NFL, likely reflecting brain white-matter alterations, characterizes clinical AD, while NFL levels do not predict age-related cognitive impairment or impending AD.
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http://dx.doi.org/10.1002/dad2.12050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311800PMC
June 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Longitudinal evidence that reduced hemispheric encoding/retrieval asymmetry predicts episodic-memory impairment in aging.

Neuropsychologia 2020 02 27;137:107329. Epub 2019 Dec 27.

Department of Radiation Sciences, Umeå University, S90187, Umeå, Sweden; Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Sweden; Department of Integrative Medical Biology, Umeå University, S90187, Umeå, Sweden.

The HERA (Hemispheric Encoding/Retrieval Asymmetry) model captures hemispheric lateralization of prefrontal cortex (PFC) brain activity during memory encoding and retrieval. Reduced HERA has been observed in cross-sectional aging studies, but there is no longitudinal evidence, to our knowledge, on age-related changes in HERA and whether maintained or reduced HERA relates to well-preserved memory functioning. In the present study we set out to explore HERA in a longitudinal neuroimaging sample from the Betula study [3 Waves over 10 years; Wave-1: n = 363, W2: n = 227, W3: n = 101]. We used fMRI data from a face-name paired-associates task to derive a HERA index. In support of the HERA model, the mean HERA index was positive across the three imaging waves. The longitudinal age-HERA relationship was highly significant (p < 10), with a HERA decline occurring after age 60. The age-related HERA decline was associated with episodic memory decline (p < 0.05). Taken together, the findings provide large-scale support for the HERA model, and suggest that reduced HERA in the PFC reflects pathological memory aging possibly related to impaired ability to bias mnemonic processing according to the appropriate encoding or retrieval state.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107329DOI Listing
February 2020

Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging.

Front Mol Neurosci 2019 25;12:229. Epub 2019 Sep 25.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Hippocampal - as well as -activation have been reported during memory encoding in older individuals. Prefrontal cortex (PFC) provides top-down state signals to the hippocampus that bias its computation during memory encoding and retrieval, and disturbed top-down signals could contribute to hippocampal hyper-activation. Here, we used >500 cross-sectional and longitudinal observations from a face-name encoding-retrieval fMRI task to examine hippocampal hypo- and hyper-activation in aging. Age-related anterior hippocampal hypo-activation was observed during memory encoding. Next, older individuals who longitudinally dropped-out were compared with those who remained in the study. Older dropouts had lower memory performance and higher dementia risk, and hyper-activated right anterior and posterior hippocampus during memory encoding. During encoding, the dropouts also activated right prefrontal regions that instead were active during retrieval in younger and older remainers. Moreover, the dropouts showed altered frontal-hippocampal functional connectivity, notably elevated right PFC to anterior hippocampus (aHC) connectivity during encoding. In the context of a general pattern of age-related anterior hippocampal hypo-activation during encoding, these findings support a top-down contribution to paradoxically high anterior hippocampal activity in older dropouts who were at elevated risk of pathology.
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http://dx.doi.org/10.3389/fnmol.2019.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798051PMC
September 2019

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition.

JAMA Psychiatry 2020 04;77(4):420-430

Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, Setting, And Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main Outcomes And Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions And Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.3779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822096PMC
April 2020

Cardiovascular factors are related to dopamine integrity and cognition in aging.

Ann Clin Transl Neurol 2019 11 30;6(11):2291-2303. Epub 2019 Oct 30.

Department of Radiation Sciences, Diagnostic Radiology, Umeå University, S-90187, Umeå, Sweden.

Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age-related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

Methods: The present work used magnetic resonance imaging and positron emission tomography with C-raclopride to jointly examine vascular parameters (white-matter lesions and perfusion), DA D2-receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging (COBRA) study.

Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White-matter lesion burden was negatively correlated with caudate DA D2-receptor availability and white-matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2-receptor availability, white-matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey-matter volumes, a larger number of white-matter lesions, and lower episodic memory performance.

Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age-sensitive cognitive functions, with emphasis on DA integrity.
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http://dx.doi.org/10.1002/acn3.50927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856613PMC
November 2019

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

High long-term test-retest reliability for extrastriatal C-raclopride binding in healthy older adults.

J Cereb Blood Flow Metab 2020 09 10;40(9):1859-1868. Epub 2019 Sep 10.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal C-raclopride binding potential (BP) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal C-raclopride BP values in healthy, older adults (n = 27, age: 64-78 years). Mean C-raclopride BP values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional C-raclopride BP values correlated with previously determined F-fallypride BP values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal C-raclopride measurements represent a true D2 signal.
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http://dx.doi.org/10.1177/0271678X19874770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446562PMC
September 2020

Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning.

Cereb Cortex 2020 03;30(3):989-1000

Aging Research Center, Karolinska Institute and Stockholm University, S-17177 Stockholm, Sweden.

Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.
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http://dx.doi.org/10.1093/cercor/bhz142DOI Listing
March 2020

Mapping the landscape of human dopamine D2/3 receptors with [C]raclopride.

Brain Struct Funct 2019 Nov 23;224(8):2871-2882. Epub 2019 Aug 23.

Aging Research Center, Karolinska Institutet and Stockholm University, Tomtebodavägen 18A, 171 65, Solna, Sweden.

The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BP in the extrastriatal regions with [C]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.
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http://dx.doi.org/10.1007/s00429-019-01938-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778542PMC
November 2019

The Influence of Hippocampal Dopamine D2 Receptors on Episodic Memory Is Modulated by and Polymorphisms.

J Cogn Neurosci 2019 09 21;31(9):1422-1429. Epub 2019 May 21.

Karolinska Institute and Stockholm University.

Episodic memory is a polygenic trait influenced by different molecular mechanisms. We used PET and a candidate gene approach to investigate how individual differences at the molecular level translate into between-person differences in episodic memory performance of elderly persons. Specifically, we examined the interactive effects between hippocampal dopamine D2 receptor (D2DR) availability and candidate genes relevant for hippocampus-related memory functioning. We show that the positive effects of high D2DR availability in the hippocampus on episodic memory are confined to carriers of advantageous genotypes of the brain-derived neurotrophic factor (, rs6265) and the kidney and brain expressed protein (, rs17070145) polymorphisms. By contrast, these polymorphisms did not modulate the positive relationship between caudate D2DR availability and episodic memory.
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http://dx.doi.org/10.1162/jocn_a_01429DOI Listing
September 2019

The supplementary motor area syndrome and cognitive control.

Neuropsychologia 2019 06 28;129:141-145. Epub 2019 Mar 28.

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, S-901 87, Umeå, Sweden; Department of Integrative Medical Biology, Umeå University, S-901 87, Umeå, Sweden.

The Supplementary Motor Area (SMA)-syndrome is a transient disturbance of the ability to initiate voluntary motor and speech actions that will often occur immediately after neurosurgical resections in the dorsal superior frontal gyrus but will typically have disappeared after 3 months. The purpose of the present study was to investigate the extent to which this syndrome is associated with alterations in cognitive control. Five patients who were to different extents affected by the SMA-syndrome after surgery for WHO grade II gliomas in the left hemisphere, were tested with the color word interference (Stroop) test; the Bergen dichotic listening test and for letter and category verbal fluency before surgery, 1-2 days after surgery and approximately 3 months after surgery. Results suggest that the motor symptoms known as the SMA syndrome co-occur with pronounced deficits in cognitive control.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.03.013DOI Listing
June 2019

Dopamine D Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.

J Neurosci 2019 01 26;39(3):537-547. Epub 2018 Nov 26.

Umeå Center for Functional Brain Imaging.

Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA-BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) -back task along with DA D PET assessment using [C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D receptors to BOLD response in the thalamo-striatal-cortical circuit, which supports WM functioning. Critically, the DA-BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA-BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA-BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks. Dopamine (DA) is a major neuromodulator in the CNS and plays a key role in several cognitive processes via modulating the blood oxygenation level-dependent (BOLD) signal. Some studies have shown a link between DA and BOLD, whereas others have failed to observe such a relationship. A possible reason for the discrepancy is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. We examined the relationship of DA to BOLD response during working memory under three load conditions and found that the DA-BOLD association is expressed in a load-dependent fashion. These findings may help explain the disproportionate impairment evident in more effortful cognitive tasks in normal aging and in those suffering dopamine-dependent neurodegenerative diseases (e.g., Parkinson's disease).
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http://dx.doi.org/10.1523/JNEUROSCI.1493-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335744PMC
January 2019

C957T-mediated Variation in Ligand Affinity Affects the Association between C-raclopride Binding Potential and Cognition.

J Cogn Neurosci 2019 02 8;31(2):314-325. Epub 2018 Nov 8.

Umeå University.

The dopamine (DA) system plays an important role in cognition. Accordingly, normal variation in DA genes has been found to predict individual differences in cognitive performance. However, little is known of the impact of genetic differences on the link between empirical indicators of the DA system and cognition in humans. The present work used PET with C-raclopride to assess DA D2-receptor binding potential (BP) and links to episodic memory, working memory, and perceptual speed in 179 healthy adults aged 64-68 years. Previously, the T-allele of a DA D2-receptor single-nucleotide polymorphism, C957T, was associated with increased apparent affinity of C-raclopride, giving rise to higher BP values despite similar receptor density values between allelic groups. Consequently, we hypothesized that C-raclopride BP measures inflated by affinity rather than D2-receptor density in T-allele carriers would not be predictive of DA integrity and therefore prevent finding an association between C-raclopride BP and cognitive performance. In accordance with previous findings, we show that C-raclopride BP was increased in T-homozygotes. Importantly, C-raclopride BP was only associated with cognitive performance in groups with low or average ligand affinity (C-allele carriers of C957T, n = 124), but not in the high-affinity group (T-homozygotes, n = 55). The strongest C-raclopride BP-cognition associations and the highest level of performance were found in C-homozygotes. These findings show that genetic differences modulate the link between BP and cognition and thus have important implications for the interpretation of DA assessments with PET and C-raclopride in multiple disciplines ranging from cognitive neuroscience to psychiatry and neurology.
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http://dx.doi.org/10.1162/jocn_a_01354DOI Listing
February 2019

Self-rated intensity of habitual physical activities is positively associated with dopamine D receptor availability and cognition.

Neuroimage 2018 11 21;181:605-616. Epub 2018 Jul 21.

Aging Research Center, Karolinska Institutet and Stockholm University, S-11330, Stockholm, Sweden.

Between-person differences in cognitive performance in older age are associated with variations in physical activity. The neurotransmitter dopamine (DA) contributes to cognitive performance, and the DA system deteriorates with advancing age. Animal data and a patient study suggest that physical activity modulates DA receptor availability, but data from healthy humans are lacking. In a cross-sectional study with 178 adults aged 64-68 years, we investigated links among self-reported physical activity, D2/D3 DA receptor (DDR) availability, and cognitive performance. DDR availability was measured with [C]raclopride positron emission tomography at rest. We used structural equation modeling to obtain latent factors for processing speed, episodic memory, working memory, physical activity, and DDR availability in caudate, putamen, and hippocampus. Physical activity intensity was positively associated with DDR availability in caudate, but not putamen and hippocampus. Frequency of physical activity was not related to DDR availability. Physical activity intensity was positively related to episodic memory and working memory. DDR availability in caudate and hippocampus was positively related to episodic memory. Taken together, our results suggest that striatal DA availability might be a neurochemical correlate of episodic memory that is also associated with physical activity.
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http://dx.doi.org/10.1016/j.neuroimage.2018.07.036DOI Listing
November 2018

Neurocognitive Profiles of Older Adults with Working-Memory Dysfunction.

Cereb Cortex 2018 07;28(7):2525-2539

Umeå Center for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden.

Individuals differ in how they perceive, remember, and think. There is evidence for the existence of distinct subgroups that differ in cognitive performance within the older population. However, it is less clear how individual differences in cognition in old age are linked to differences in brain-based measures. We used latent-profile analysis on n-back working-memory (WM) performance to identify subgroups in a large sample of older adults (n = 181; age = 64-68 years). Our analysis identified one larger normal subgroup with higher performance (n = 113; 63%), and a second smaller subgroup (n = 55; 31%) with lower performance. The low-performing subgroup showed weaker load-dependent BOLD modulation and lower connectivity within the fronto-parietal network (FPN) as well as between FPN and striatum during n-back, along with lower FPN connectivity at rest. This group also exhibited lower FPN structural integrity, lower frontal dopamine D2 binding potential, inferior performance on offline WM tests, and a trend-level genetic predisposition for lower dopamine-system efficiency. By contrast, this group exhibited relatively intact episodic memory and associated brain measures (i.e., hippocampal volume, structural, and functional connectivity within the default-mode network). Collectively, these data provide converging evidence for the existence of a group of older adults with impaired WM functioning characterized by reduced cortico-striatal coupling and aberrant cortico-cortical integrity within FPN.
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http://dx.doi.org/10.1093/cercor/bhy062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998950PMC
July 2018

Neural activations associated with feedback and retrieval success.

NPJ Sci Learn 2017 2;2:12. Epub 2017 Nov 2.

2Umeå Center for Function Brain Imaging (UFBI), Umeå University, Umeå, Sweden.

There is substantial behavioral evidence for a phenomenon commonly called "", i.e. superior memory performance after repeated testing compared to re-study of to-be-learned materials. However, considerably less is known about the underlying neuro-cognitive processes that are involved in the initial testing phase, and thus underlies the actual testing effect. Here, we investigated functional brain activity related to test-enhanced learning with feedback. Subjects learned foreign vocabulary across three consecutive tests with correct-answer feedback. Functional brain-activity responses were analyzed in relation to retrieval and feedback events, respectively. Results revealed up-regulated activity in fronto-striatal regions during the first successful retrieval, followed by a marked reduction in activity as a function of improved learning. Whereas feedback improved behavioral performance across consecutive tests, feedback had a negligable role after the first successful retrieval for functional brain-activity modulations. It is suggested that the beneficial effects of test-enhanced learning is regulated by feedback-induced updating of memory representations, mediated via the striatum, that might underlie the stabilization of memory commonly seen in behavioral studies of the testing effect.
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http://dx.doi.org/10.1038/s41539-017-0013-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161507PMC
November 2017

Latent-Profile Analysis Reveals Behavioral and Brain Correlates of Dopamine-Cognition Associations.

Cereb Cortex 2018 11;28(11):3894-3907

Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany.

Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64-68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D2/3R availability (probed with 11C-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.
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http://dx.doi.org/10.1093/cercor/bhx253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823239PMC
November 2018

Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: Changes Linked to Altered Striato-Thalamic-Cortical Functioning.

J Head Trauma Rehabil 2018 Jul/Aug;33(4):266-274

Department of Community Medicine and Rehabilitation, Geriatric Medicine (Mr Berginström and Dr Nordström), Umeå Center for Functional Brain Imaging and Physiology Section, Department of Integrative Medical Biology (Drs Ekman, Eriksson, and Nyberg and Mr Andersson), Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine (Dr Nordström), and Department of Radiation Sciences (Dr Nyberg) Umeå University, Umeå, Sweden; and Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden (Dr Ekman).

Objective: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI).

Setting: Neurorehabilitation clinic.

Participants: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27).

Main Measures: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task.

Results: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001). The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%.

Conclusion: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.
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http://dx.doi.org/10.1097/HTR.0000000000000340DOI Listing
August 2019

Neural activation in stress-related exhaustion: Cross-sectional observations and interventional effects.

Psychiatry Res Neuroimaging 2017 Nov 14;269:17-25. Epub 2017 Sep 14.

Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå, Sweden; Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Denmark; Centre for Demographic and Aging Research (CEDAR), Umeå University, Umeå, Sweden.

The primary purpose of this study was to investigate the association between burnout and neural activation during working memory processing in patients with stress-related exhaustion. Additionally, we investigated the neural effects of cognitive training as part of stress rehabilitation. Fifty-five patients with clinical diagnosis of exhaustion disorder were administered the n-back task during fMRI scanning at baseline. Ten patients completed a 12-week cognitive training intervention, as an addition to stress rehabilitation. Eleven patients served as a treatment-as-usual control group. At baseline, burnout level was positively associated with neural activation in the rostral prefrontal cortex, the posterior parietal cortex and the striatum, primarily in the 2-back condition. Following stress rehabilitation, the striatal activity decreased as a function of improved levels of burnout. No significant association between burnout level and working memory performance was found, however, our findings indicate that frontostriatal neural responses related to working memory were modulated by burnout severity. We suggest that patients with high levels of burnout need to recruit additional cognitive resources to uphold task performance. Following cognitive training, increased neural activation was observed during 3-back in working memory-related regions, including the striatum, however, low sample size limits any firm conclusions.
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http://dx.doi.org/10.1016/j.pscychresns.2017.08.008DOI Listing
November 2017

Increased dopamine release after working-memory updating training: Neurochemical correlates of transfer.

Sci Rep 2017 08 2;7(1):7160. Epub 2017 Aug 2.

Department of Radiation Sciences, Umeå University, Umeå, Sweden.

Previous work demonstrates that working-memory (WM) updating training results in improved performance on a letter-memory criterion task, transfers to an untrained n-back task, and increases striatal dopamine (DA) activity during the criterion task. Here, we sought to replicate and extend these findings by also examining neurochemical correlates of transfer. Four positron emission tomography (PET) scans using the radioligand raclopride were performed. Two of these assessed DAD2 binding (letter memory; n-back) before 5 weeks of updating training, and the same two scans were performed post training. Key findings were (a) pronounced training-related behavioral gains in the letter-memory criterion task, (b) altered striatal DAD2 binding potential after training during letter-memory performance, suggesting training-induced increases in DA release, and (c) increased striatal DA activity also during the n-back transfer task after the intervention, but no concomitant behavioral transfer. The fact that the training-related DA alterations during the transfer task were not accompanied by behavioral transfer suggests that increased DA release may be a necessary, but not sufficient, condition for behavioral transfer to occur.
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http://dx.doi.org/10.1038/s41598-017-07577-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540932PMC
August 2017
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