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  • 1. Burzynska, Agnieszka Z.
    et al.
    Garrett, Douglas D.
    Preuschhof, Claudia
    Nagel, Irene E.
    Li, Shu-Chen
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Heekeren, Hauke R.
    Lindenberger, Ulman
    A Scaffold for Efficiency in the Human Brain2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 43, 17150-17159 p.Article in journal (Refereed)
    Abstract [en]

    The comprehensive relations between healthy adult human brain white matter(WM) microstructure and gray matter (GM) function, and their joint relations to cognitive performance, remain poorly understood. We investigated these associations in 27 younger and 28 older healthy adults by linking diffusion tensor imaging (DTI) with functional magnetic resonance imaging (fMRI) data collected during an n-back working memory task. We present a novel application of multivariate Partial Least Squares (PLS) analysis that permitted the simultaneous modeling of relations between WM integrity values from all major WM tracts and patterns of condition-related BOLD signal across all GM regions. Our results indicate that greater microstructural integrity of the major WM tracts was negatively related to condition-related blood oxygenation level-dependent (BOLD) signal in task-positive GM regions. This negative relationship suggests that better quality of structural connections allows for more efficient use of task-related GM processing resources. Individuals with more intact WM further showed greater BOLD signal increases in typical task-negative regions during fixation, and notably exhibited a balanced magnitude of BOLD response across task-positive and-negative states. Structure-function relations also predicted task performance, including accuracy and speed of responding. Finally, structure-function behavior relations reflected individual differences over and above chronological age. Our findings provide evidence for the role of WM microstructure as a scaffold for the context-relevant utilization of GM regions.

  • 2. Economides, Marcos
    et al.
    Guitart-Masip, Marc
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, England.
    Kurth-Nelson, Zeb
    Dolan, Raymond J.
    Anterior Cingulate Cortex Instigates Adaptive Switches in Choice by Integrating Immediate and Delayed Components of Value in Ventromedial Prefrontal Cortex2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 9, 3340-3349 p.Article in journal (Refereed)
    Abstract [en]

    Actions can lead to an immediate reward or punishment and a complex set of delayed outcomes. Adaptive choice necessitates the brain track and integrate both of these potential consequences. Here, we designed a sequential task whereby the decision to exploit or forego an available offer was contingent on comparing immediate value and a state-dependent future cost of expending a limited resource. Crucially, the dynamics of the task demanded frequent switches in policy based on an online computation of changing delayed consequences. We found that human subjects choose on the basis of a near-optimal integration of immediate reward and delayed consequences, with the latter computed in a prefrontal network. Within this network, anterior cingulate cortex (ACC) was dynamically coupled to ventromedial prefrontal cortex (vmPFC) when adaptive switches in choice were required. Our results suggest a choice architecture whereby interactions between ACC and vmPFC underpin an integration of immediate and delayed components of value to support flexible policy switching that accommodates the potential delayed consequences of an action.

  • 3. Eketjäll, Susanna
    et al.
    Jeppsson, Fredrik
    Innovative Medicines AstraZeneca, CNS & Pain, Södertälje, Sweden.
    Fälting, Johanna
    AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 24, 10075-10084 p.Article in journal (Refereed)
    Abstract [en]

    A beta, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). beta-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to A beta peptides. Small molecule BACE1 inhibitors are expected to decrease A beta-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of A beta production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

  • 4. Fiebig, Florian
    et al.
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    A Spiking Working Memory Model Based on Hebbian Short-Term Potentiation2017In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 37, no 1, 83-96 p.Article in journal (Refereed)
    Abstract [en]

    A dominant theory of working memory (WM), referred to as the persistent activity hypothesis, holds that recurrently connected neural networks, presumably located in the prefrontal cortex, encode and maintain WM memory items through sustained elevated activity. Reexamination of experimental data has shown that prefrontal cortex activity in single units during delay periods is much more variable than predicted by such a theory and associated computational models. Alternative models of WM maintenance based on synaptic plasticity, such as short-term nonassociative (non-Hebbian) synaptic facilitation, have been suggested but cannot account for encoding of novel associations. Here we test the hypothesis that a recently identified fast-expressing form of Hebbian synaptic plasticity (associative short-term potentiation) is a possible mechanism for WM encoding and maintenance. Our simulations using a spiking neural network model of cortex reproduce a range of cognitive memory effects in the classical multi-item WM task of encoding and immediate free recall of word lists. Memory reactivation in the model occurs in discrete oscillatory bursts rather than as sustained activity. We relate dynamic network activity as well as key synaptic characteristics to electrophysiological measurements. Our findings support the hypothesis that fast Hebbian short-term potentiation is a key WM mechanism.

  • 5. Fossat, P.
    et al.
    Dobremez, E.
    Bouali-Benazzouz, R.
    Favereaux, A.
    Bertrand, S. S.
    Kilk, Kalle
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Leger, C.
    Cazalets, J-R
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
    Landry, M.
    Nagy, F.
    Knockdown of L calcium channel subtypes: differential effects in neuropathic pain2010In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 30, no 3, 1073-1085 p.Article, review/survey (Refereed)
    Abstract [en]

    The maintenance of chronic pain states requires the regulation of gene expression, which relies on an influx of calcium. Calcium influx through neuronal L-type voltage-gated calcium channels (LTCs) plays a pivotal role in excitation-transcription coupling, but the involvement of LTCs in chronic pain remains unclear. We used a peptide nucleic acid (transportan 10-PNA conjugates)-based antisense strategy to investigate the role of the LTC subtypes Ca(V)1.2 and Ca(V)1.3 in long-term pain sensitization in a rat model of neuropathy (spinal nerve ligation). Our results demonstrate that specific knockdown of Ca(V)1.2 in the spinal dorsal horn reversed the neuropathy-associated mechanical hypersensitivity and the hyperexcitability and increased responsiveness of dorsal horn neurons. Intrathecal application of anti-Ca(V)1.2 siRNAs confirmed the preceding results. We also demonstrated an upregulation of Ca(V)1.2 mRNA and protein in neuropathic animals concomitant to specific Ca(V)1.2-dependent phosphorylation of the cAMP response element (CRE)-binding protein (CREB) transcription factor. Moreover, spinal nerve ligation animals showed enhanced transcription of the CREB/CRE-dependent gene COX-2 (cyclooxygenase 2), which also depends strictly on Ca(V)1.2 activation. We propose that L-type calcium channels in the spinal dorsal horn play an important role in pain processing, and that the maintenance of chronic neuropathic pain depends specifically on channels comprising Ca(V)1.2.

  • 6. Hermann-Luibl, Christiane
    et al.
    Yoshii, Taishi
    Senthilan, Pingkalai R.
    Dircksen, Heinrich
    Stockholm University, Faculty of Science, Department of Zoology.
    Helfrich-Förster, Charlotte
    The Ion Transport Peptide Is a New Functional Clock Neuropeptide in the Fruit Fly Drosophila melanogaster2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 29, 9522-9536 p.Article in journal (Refereed)
    Abstract [en]

    The clock network of Drosophila melanogaster expresses various neuropeptides, but a function in clock-mediated behavioral control was so far only found for the neuropeptide pigment dispersing factor (PDF). Here, we propose a role in the control of behavioral rhythms for the ion transport peptide (ITP), which is expressed in the fifth small ventral lateral neuron, one dorsal lateral neuron, and in only a few nonclock cells in the brain. Immunocytochemical analyses revealed that ITP, like PDF, is most probably released in a rhythmic manner at projection terminals in the dorsal protocerebrum. This rhythm continues under constant dark conditions, indicating that ITP release is clock controlled. ITP expression is reduced in the hypomorph mutant ClkAR, suggesting that ITP expression is regulated by CLOCK. Using a genetically encoded RNAi construct, we knocked down ITP in the two clock cells and found that these flies show reduced evening activity and increased nocturnal activity. Overexpression of ITP with two independent timeless-GAL4 lines completely disrupted behavioral rhythms, but only slightly dampened PER cycling in important pacemaker neurons, suggesting a role for ITP in clock output pathways rather than in the communication within the clock network. Simultaneous knockdown (KD) of ITP and PDF made the flies hyperactive and almost completely arrhythmic under constant conditions. Under light-dark conditions, the double-KD combined the behavioral characteristics of the single-KD flies. In addition, it reduced the flies' sleep. We conclude that ITP and PDF are the clock's main output signals that cooperate in controlling the flies' activity rhythms.

  • 7. Kantrowitz, Joshua T.
    et al.
    Hoptman, Matthew J.
    Leitman, David I.
    Moreno-Ortega, Marta
    Lehrfeld, Jonathan M.
    Dias, Elisa
    Sehatpour, Pejman
    Laukka, Petri
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Silipo, Gail
    Javitt, Daniel C.
    Neural Substrates of Auditory Emotion Recognition Deficits in Schizophrenia2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 44, 14909-14921 p.Article in journal (Refereed)
    Abstract [en]

    Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal (“prosodic”) features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and rsfMRI was assessed in the subset who performed all assessments (14 patients, 21 controls). As predicted, patients showed robust reductions in MMN across FM stimulus type (p = 0.005), particularly to modulations in F0M, along with impairments in AER and FM tone discrimination. MMN source analysis indicated dipoles in both auditory cortex and anterior insula, whereas rsfMRI analyses showed reduced auditory-insula connectivity. MMN to FM tones and functional connectivity together accounted for ∼50% of the variance in AER performance across individuals. These findings demonstrate that impaired preattentive processing of tonal information and reduced auditory-insula connectivity are critical determinants of social cognitive dysfunction in schizophrenia, and thus represent key targets for future research and clinical intervention.

  • 8. Kauppi, Karolina
    et al.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Adolfsson, Rolf
    Eriksson, Elias
    Nyberg, Lars
    KIBRA Polymorphism Is Related to Enhanced Memory and Elevated Hippocampal Processing2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 40, 14218-14222 p.Article in journal (Refereed)
    Abstract [en]

    Several studies have linked the KIBRA rs17070145 T polymorphism to superior episodic memory in healthy humans. One study investigated the effect of KIBRA on brain activation patterns (Papassotiropoulos et al., 2006) and observed increased hippocampal activation in noncarriers of the T allele during retrieval. Noncarriers were interpreted to need more hippocampal activation to reach the same performance level as T carriers. Using large behavioral (N = 2230) and fMRI (N = 83) samples, we replicated the KIBRA effect on episodic memory performance, but found increased hippocampal activation in T carriers during episodic retrieval. There was no evidence of compensatory brain activation in noncarriers within the hippocampal region. In the main fMRI sample, T carriers performed better than noncarriers during scanning but, importantly, the difference in hippocampus activation remained after post hoc matching according to performance, sex, and age (N = 64). These findings link enhanced memory performance in KIBRA T allele carriers to elevated hippocampal functioning, rather than to neural compensation in noncarriers.

  • 9. Knapek, Stephan
    et al.
    Kahsai, Lily
    Stockholm University, Faculty of Science, Department of Zoology.
    Winther, Åsa M. E.
    Stockholm University, Faculty of Science, Department of Zoology.
    Tanimoto, Hiromu
    Nässel, Dick R.
    Stockholm University, Faculty of Science, Department of Zoology.
    Short Neuropeptide F Acts as a Functional Neuromodulator for Olfactory Memory in Kenyon Cells of Drosophila Mushroom Bodies2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 12, 5340-+ p.Article in journal (Refereed)
    Abstract [en]

    In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside theMBcauses deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

  • 10.
    Lundqvist, Mikael
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Herman, Pawel
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Effect of Prestimulus Alpha Power, Phase, and Synchronization on Stimulus Detection Rates in a Biophysical Attractor Network Model2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 29, 11817-+ p.Article in journal (Refereed)
    Abstract [en]

    Spontaneous oscillations measured by local field potentials, electroencephalograms and magnetoencephalograms exhibit a pronounced peak in the alpha band (8-12 Hz) in humans and primates. Both instantaneous power and phase of these ongoing oscillations have commonly been observed to correlate with psychophysical performance in stimulus detection tasks. We use a novel model-based approach to study the effect of prestimulus oscillations on detection rate. A previously developed biophysically detailed attractor network exhibits spontaneous oscillations in the alpha range before a stimulus is presented and transiently switches to gamma-like oscillations on successful detection. We demonstrate that both phase and power of the ongoing alpha oscillations modulate the probability of such state transitions. The power can either positively or negatively correlate with the detection rate, in agreement with experimental findings, depending on the underlying neural mechanism modulating the oscillatory power. Furthermore, the spatially distributed alpha oscillators of the network can be synchronized by global nonspecific weak excitatory signals. These synchronization events lead to transient increases in alpha-band power and render the network sensitive to the exact timing of target stimuli, making the alpha cycle function as a temporal mask in line with recent experimental observations. Our results are relevant to several studies that attribute a modulatory role to prestimulus alpha dynamics.

  • 11. MacDonald, Stuart W S
    et al.
    Karlsson, Sari
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rieckmann, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Nyberg, Lars
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Aging-related increases in behavioral variability: relations to losses of dopamine D1 receptors2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 24, 8186-8191 p.Article in journal (Refereed)
    Abstract [en]

    Intraindividual variability (IIV) reflects within-person changes in performance, such as trial-by-trial fluctuations on a reaction-time (RT) task. The neural underpinnings of IIV remain largely unknown. The neurotransmitter dopamine (DA) is of particular interest here, as human populations that exhibit DA alterations, such as the elderly, attention deficit hyperactivity disorder children, persons with schizophrenia, and Parkinson patients, also show increased behavioral IIV. We examined links between DA D(1) binding potential (BP) in multiple brain regions and IIV for the control and interference conditions of the Multi-Source Interference Task (MSIT), tapping the cingulo-fronto-parietal attention network. Participants were 18 young and 20 healthy old adults. PET and the radioligand [(11)C]SCH23390 were used to determine D(1) BP. The intraindividual standard deviation (ISD) was computed across successful latency trials of the MSIT conditions, independent of mean RT differences due to age, trial, and condition. Increasing ISDs were associated with increasing age and diminished D(1) binding in several brain regions (anterior cingulate gyrus, dorsolateral prefrontal cortex, and parietal cortex) for the interference, but not control, condition. Analyses of partial associations indicate that the association between age and IIV in the interference condition was linked to D(1) receptor losses in task-relevant brain regions. These findings suggest that dysfunctional DA modulation may contribute to increased variability in cognitive performance among older adults.

  • 12. Nair, Anu G.
    et al.
    Gutierrez-Arenas, Omar
    Eriksson, Olivia
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab).
    Vincent, Pierre
    Hellgren Kotaleski, Jeanette
    Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 41, 14017-14030 p.Article in journal (Refereed)
    Abstract [en]

    Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via G(olf)- and G(i/o)-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R + MSNs via ACh/M4R/G(i/o) and an ACh dip is required to gate a subset of D1R/G(olf)-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2 + MSNs is under basal inhibition via D2R/G(i/o) and a DA dip leads to a PKA increase by disinhibiting A2aR/G(olf), but D2 + MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by G(i/o) and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.

  • 13.
    Pudas, Sara
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Persson, Jonas
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Josefsson, Maria
    de Luna, Xavier
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Nyberg, Lars
    Brain characteristics of individuals resisting age-related cognitive decline over two decades2013In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 33, no 20, 8668-8677 p.Article in journal (Refereed)
    Abstract [en]

    Some elderly appear to resist age-related decline in cognitive functions, but the neural correlates of successful cognitive aging are not well known. Here, older human participants from a longitudinal study were classified as successful or average relative to the mean attrition-corrected cognitive development across 15-20 years in a population-based sample (n = 1561). Fifty-one successful elderly and 51 age-matched average elderly (mean age: 68.8 years) underwent functional magnetic resonance imaging while performing an episodic memory face-name paired-associates task. Successful older participants had higher BOLD signal during encoding than average participants, notably in the bilateral PFC and the left hippocampus (HC). The HC activation of the average, but not the successful, older group was lower than that of a young reference group (n = 45, mean age: 35.3 years). HC activation was correlated with task performance, thus likely contributing to the superior memory performance of successful older participants. The frontal BOLD response pattern might reflect individual differences present from young age. Additional analyses confirmed that both the initial cognitive level and the slope of cognitive change across the longitudinal measurement period contributed to the observed group differences in BOLD signal. Further, the differences between the older groups could not be accounted for by differences in brain structure. The current results suggest that one mechanism behind successful cognitive aging might be preservation of HC function combined with a high frontal responsivity. These findings highlight sources for heterogeneity in cognitive aging and may hold useful information for cognitive intervention studies.

  • 14.
    Rieckmann, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Karlsson, Sari
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Caudate Dopamine D1 Receptor Density Is Associated with Individual Differences in Frontoparietal Connectivity during Working Memory2011In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 40, 14284-14290 p.Article in journal (Refereed)
    Abstract [en]

    We assess the relationship of age-related losses in striatal D1 receptor densities to age-related reductions in functional connectivity between spatially distinct cortical regions in healthy human participants. Previous neuroimaging studies have reported age-related differences in functional connectivity of the frontoparietal working memory network and the default mode network during task performance. We used functional magnetic resonance imaging and seed-based connectivity (right dorsolateral and medial prefrontal cortex) to extend these findings: Anterior-posterior connectivity of both these functional networks was reduced in older (65-75 years, n = 18) compared with younger (20-30 years, n = 19) adults, whereas bilateral connectivity in prefrontal cortex was increased in older adults. Positron emission tomography with the D1 receptor ligand [(11)C]SCH23390 was used to assess caudate D1 receptor density in the same sample. Older adults showed significantly reduced caudate D1 receptor density compared to the younger adults. Of key interest, partial correlations showed that individual differences in caudate D1 receptor density were positively associated with individual differences in dorsolateral prefrontal connectivity to right parietal cortex (BA40) and negatively with medial prefrontal connectivity to right parietal cortex (BA40 and postcentral gyrus), after controlling for age. We found no correlation of caudate D1 receptor density with anterior-posterior coupling within the default mode network or with bilateral frontal connectivity. These results are consistent with animal work that has identified a role for caudate D1 receptors in mediating information transfer between prefrontal areas and parietal cortex.

  • 15.
    Rieckmann, Anna
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Karlsson, Sari
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Increased Bilateral Frontal Connectivity during Working Memory in Young Adults under the Influence of a Dopamine D1 Receptor Antagonist2012In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 48, 17067-17072 p.Article in journal (Refereed)
    Abstract [en]

    Increased frontal bilaterality in old compared with young adults during cognitive performance is a common finding in human functional neuroimaging studies. Age-related reductions in laterality are a widely debated topic and their origins and consequences may be manifold. The current study demonstrates that a dopamine (DA) D1 antagonist induces increased frontal bilateral connectivity in healthy young adults revealed by functional magnetic resonance imaging during a spatial working memory task. Moreover, increases in functional connectivity between right and left prefrontal cortex during the pharmacological challenge were associated with maintaining performance on drug. To our knowledge, this is the first study to pharmacologically induce increased frontal bilateral functional connectivity during a cognitive task in young adults and to show that increased bilaterality is associated with less severe cognitive impairment under the influence of a DA receptor antagonist.

  • 16. Rypma, Bart
    et al.
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Rieckmann, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Hubbard, Nicholas A.
    Nyberg, Lars
    Bäckman, Lars
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Dopamine D1 Binding Potential Predicts Fusiform BOLD Activity during Face-Recognition Performance2015In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 35, no 44, 14702-14707 p.Article in journal (Refereed)
    Abstract [en]

    The importance of face memory in humans and primates is well established, but little is known about the neurotransmitter systems involved in face recognition. We tested the hypothesis that face recognition is linked to dopamine (DA) activity in fusiform gyrus (FFG). DA availability was assessed by measuring D1 binding potential (BP) during rest using PET. We further assessed blood-oxygen-level-dependent (BOLD) signal change while subjects performed a face-recognition task during fMRI scanning. There was a strong association between D1 BP and BOLD activity in FFG, whereasD1BPin striatal and other extrastriatal regions were unrelated to neural activity in FFG. These results suggest that D1 BP locally modulates FFG function during face recognition. Observed relationships among D1 BP, BOLD activity, and face-recognition performance further suggest that D1 receptors place constraints on the responsiveness of FFG neurons.

  • 17. Werkle-Bergner, Markus
    et al.
    Grandy, Thomas H.
    Chicherio, Christian
    Schmiedek, Florian
    Lövdén, Martin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Max Planck Society, Germany.
    Lindenberger, Ulman
    Coordinated within-Trial Dynamics of Low-Frequency Neural Rhythms Controls Evidence Accumulation2014In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 34, no 25, 8519-8528 p.Article in journal (Refereed)
    Abstract [en]

    Higher cognitive functions, such as human perceptual decision making, require information processing and transmission across widespread cortical networks. Temporally synchronized neural firing patterns are advantageous for efficiently representing and transmitting information within and between assemblies. Computational, empirical, and conceptual considerations all lead to the expectation that the informational redundancy of neural firing rates is positively related to their synchronization. Recent theorizing and initial evidence also suggest that the coding of stimulus characteristics and their integration with behavioral goal states require neural interactions across a hierarchy of timescales. However, most studies thus have focused on neural activity in a single frequency range or on a restricted set of brain regions. Here we provide evidence for cooperative spatiotemporal dynamics of slow and fast EEG signals during perceptual decision making at the single-trial level. Participants performed three masked two-choice decision tasks, one each with numerical, verbal, or figural content. Decrements in posterior alpha power (8 - 14 Hz) were paralleled by increments in high-frequency (>30 Hz) signal entropy in trials demanding active sensory processing. Simultaneously, frontocentral theta power (4 - 7 Hz) increased, indicating evidence integration. The coordinated alpha/theta dynamics were tightly linked to decision speed and remarkably similar across tasks, suggesting a domain-general mechanism. In sum, we demonstrate an inverse association between decision-related changes in widespread low-frequency power and local high-frequency entropy. The cooperation among mechanisms captured by these changes enhances the informational density of neural response patterns and qualifies as a neural coding system in the service of perceptual decision making.

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