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  • 1.
    Ahs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sollers, John J
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Thayer, Julian F
    High-frequency heart rate variability and cortico-striatal activity in men and women with social phobia2009In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 47, no 3, p. 815-820Article in journal (Refereed)
    Abstract [en]

    Identifying brain systems that regulate or modulate autonomic nervous system functions may identify pathways through which psychosocial factors can influence health and disease. Reduced high-frequency heart rate variability (HF-HRV) characterizes anxiety disordered patients and is predictive of adverse myocardial events. Sex differences in the prevalence of anxiety disorders and cardiac diseases implicate the possibility of sex specific neural regulation of HF-HRV. We investigated the correlation between HF-HRV and regional cerebral blood flow (rCBF) in 28 subjects (15 women) with social phobia undergoing a stressful public speaking task. Regional CBF was measured with [(15)O] water positron emission tomography. Stress induced rCBF correlated positively with HF-HRV in the right supra genual anterior cingulate cortex Brodmann's area (BA) 32, the right head of the caudate nucleus and bilaterally in the medial prefrontal cortex (BA10), extending into the dorsolateral prefrontal cortex (BA46) in the left hemisphere. Men showed larger positive co-variation in the caudate than women. These findings underscore the importance of the emotional division of the anterior cingulate cortex, the prefrontal cortex and the striatum in cardiovagal activity. The study replicates and extends results from published functional neuroimaging studies on cardioregulatory or modulatory areas in healthy subjects to men and women with social phobia. Moreover, caudate functions, possibly related to dopaminergic neurotransmission, have sexually dimorphic effects on vagal modulation of the heart.

  • 2.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Allzen, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to subliminal arousing stimuli induces robust activation in the amygdala, hippocampus, anterior cingulate, insular cortex and primary visual cortex: A systematic meta-analysis of fMRI studies2012In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 59, no 3, p. 2962-2973Article, review/survey (Refereed)
    Abstract [en]

    Functional Magnetic Resonance Imaging (fMRI) demonstrates that the subliminal presentation of arousing stimuli can activate subcortical brain regions independently of consciousness-generating top-down cortical modulation loops. Delineating these processes may elucidate mechanisms for arousal, aberration in which may underlie some psychiatric conditions. Here we are the first to review and discuss four Activation Likelihood Estimation (ALE) meta-analyses of fMRI studies using subliminal paradigms. We find a maximum of 9 out of 12 studies using subliminal presentation of faces contributing to activation of the amygdala, and also a significantly high number of studies reporting activation in the bilateral anterior cingulate, bilateral insular cortex, hippocampus and primary visual cortex. Subliminal faces are the strongest modality, whereas lexical stimuli are the weakest. Meta-analyses independent of studies using Regions of Interest (ROI) revealed no biasing effect Core neuronal arousal in the brain, which may be at first independent of conscious processing, potentially involves a network incorporating primary visual areas, somatosensory, implicit memory and conflict monitoring regions. These data could provide candidate brain regions for the study of psychiatric disorders associated with aberrant automatic emotional processing.

  • 3.
    Emmert, Kirsten
    et al.
    Univ Geneva, Dept Radiol & Med Informat, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Lausanne, Switzerland..
    Kopel, Rotem
    Univ Geneva, Dept Radiol & Med Informat, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Lausanne, Switzerland..
    Sulzer, James
    Univ Texas Austin, Dept Mech Engn, Austin, TX 78712 USA..
    Bruehl, Annette B.
    Univ Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, Zurich, Switzerland.;Univ Cambridge, Behav & Clin Neurosci Inst, Dept Psychiat, Cambridge, England..
    Berman, Brian D.
    Univ Colorado, Dept Neurol, Aurora, CO USA..
    Linden, David E. J.
    Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales..
    Horovitz, Silvina G.
    NINDS, NIH, Bethesda, MD 20892 USA..
    Breimhorst, Markus
    Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Neurol, D-55122 Mainz, Germany..
    Caria, Andrea
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany..
    Frank, Sabine
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany..
    Johnston, Stephen
    Long, Zhiying
    Swansea Univ, Dept Psychol, Swansea, W Glam, Wales.;Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China.;Beijing Normal Univ, IDG McGovern Inst Brain Res, Beijing 100875, Peoples R China..
    Paret, Christian
    Heidelberg Univ Mannheim, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Dept Psychosomat Med & Psychotherapy, Mannheim, Germany.;Heidelberg Univ Mannheim, Med Fac Mannheim, Cent Inst Mental Hlth Mannheim, Dept Neuroimaging, Mannheim, Germany..
    Robineau, Fabien
    Univ Geneva, Dept Neurosci, Lab Neurol & Imaging Cognit, CH-1211 Geneva 4, Switzerland..
    Veit, Ralf
    Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany.;Univ Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany..
    Bartsch, Andreas
    Heidelberg Univ, Dept Neuroradiol, Heidelberg, Germany.;Univ Wurzburg, Dept Neuroradiol, D-97070 Wurzburg, Germany.;Univ Oxford, FMRIB Ctr, Oxford, England.;Bamberg Hosp, Dept Radiol, Bamberg, Germany..
    Beckmann, Christian F.
    Radboud Univ Nijmegen, Ctr Cognit Neuroimaging, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Dept Cognit Neuroimaging, NL-6525 ED Nijmegen, Netherlands.;Univ Oxford, Oxford Ctr Funct MRI Brain, Nuffield Dept Clin Neurosci, Oxford OX1 2JD, England..
    Van De Ville, Dimitri
    Univ Geneva, Dept Radiol & Med Informat, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Lausanne, Switzerland..
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Affidea Ctr Diagnost Radiolog Carouge CDRC, Geneva, Switzerland.;Univ Hosp Freiburg, Dept Neuroradiol, Freiburg, Germany.;Univ Geneva, Fac Med, CH-1211 Geneva 4, Switzerland..
    Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: How is brain regulation mediated?2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 124, no Part A, p. 806-812Article in journal (Refereed)
    Abstract [en]

    An increasing number of studies using real-time fMRI neurofeedback have demonstrated that successful regulation of neural activity is possible in various brain regions. Since these studies focused on the regulated region(s), little is known about the target-independent mechanisms associated with neurofeedback-guided control of brain activation, i.e. the regulating network. While the specificity of the activation during self-regulation is an important factor, no study has effectively determined the network involved in self-regulation in general. In an effort to detect regions that are responsible for the act of brain regulation, we performed a post-hoc analysis of data involving different target regions based on studies from different research groups. We included twelve suitable studies that examined nine different target regions amounting to a total of 175 subjects and 899 neurofeedback runs. Data analysis included a standard first-(single subject, extracting main paradigm) and second-level (single subject, all runs) general linear model (GLM) analysis of all participants taking into account the individual timing. Subsequently, at the third level, a random effects model GLM included all subjects of all studies, resulting in an overall mixed effects model. Since four of the twelve studies had a reduced field of view (FoV), we repeated the same analysis in a subsample of eight studies that had a well-overlapping FoV to obtain a more global picture of self-regulation. The GLM analysis revealed that the anterior insula as well as the basal ganglia, notably the striatum, were consistently active during the regulation of brain activation across the studies. The anterior insula has been implicated in interoceptive awareness of the body and cognitive control. Basal ganglia are involved in procedural learning, visuomotor integration and other higher cognitive processes including motivation. The larger FoV analysis yielded additional activations in the anterior cingulate cortex, the dorsolateral and ventrolateral prefrontal cortex, the temporo-parietal area and the visual association areas including the temporo-occipital junction. In conclusion, we demonstrate that several key regions, such as the anterior insula and the basal ganglia, are consistently activated during self-regulation in real-time fMRI neurofeedback independent of the targeted region-ofinterest. Our results imply that if the real-time fMRI neurofeedback studies target regions of this regulation network, such as the anterior insula, care should be given whether activation changes are related to successful regulation, or related to the regulation process per se. Furthermore, future research is needed to determine how activation within this regulation network is related to neurofeedback success.

  • 4.
    Gustafsson, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Combined PET and microdialysis for in vivo estimation of drug blood-brain barrier transport and brain unbound concentrations2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 155, p. 177-186Article in journal (Refereed)
    Abstract [en]

    Methods to investigate blood-brain barrier transport and pharmacologically active drug concentrations in the human brain are limited and data translation between species is challenging. Hence, there is a need to further develop the read-out of techniques like positron emission tomography ( PET) for studying neuropharmacokinetics. PET has a high translational applicability from rodents to man and measures total drug concentrations in vivo. The aim of the present study was to investigate the possibility of translating total drug concentrations, acquired through PET, to unbound concentrations, resembling those measured in the interstitial fluid by microdialysis sampling. Simultaneous PET scanning and brain microdialysis sampling were performed in rats throughout a 60 min infusion of [N-methyl-C-11] oxycodone in combination with a therapeutic dose of oxycodone and during a 60 min follow up period after the end of infusion. The oxycodone concentrations acquired with PET were converted into unbound concentrations by compensating for brain tissue binding and brain intracellular distribution, using the unbound volume of distribution in brain (Vu, brain), and were compared to microdialysis measurements of unbound concentrations. A good congruence between the methods was observed throughout the infusion. However, an accumulating divergence in the acquired PET and microdialysis data was apparent and became more pronounced during the elimination phase, most likely due to the passage of radioactive metabolites into the brain. In conclusion, the study showed that PET can be used to translate non-invasively measured total drug concentrations into unbound concentrations as long as the contribution of radiolabelled metabolites is minor or can be compensated for.

  • 5.
    Heurling, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Buckley, Chris
    Van Laere, Koen
    Vandenberghe, Rik
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Akademiska sjukhuset.
    Parametric imaging and quantitative analysis of the PET amyloid ligand [(18)F]flutemetamol.2015In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 121, p. 184-192Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The amyloid imaging PET tracer [(18)F]flutemetamol was recently approved by regulatory authorities in the US and EU for estimation of β-amyloid neuritic plaque density in cognitively impaired patients. While the clinical assessment in line with the label is a qualitative visual assessment of 20min summation images, the aim of this work was to assess the performance of various parametric analysis methods and standardized uptake value ratio (SUVR), in comparison with arterial input based compartment modeling.

    METHODS: The cerebellar cortex was used as reference region in the generation of parametric images of binding potential (BPND) using multilinear reference tissue methods (MRTMo, MRTM, MRTM2), basis function implementations of the simplified reference tissue model (here called RPM) and the two-parameter version of SRTM (here called RPM2) and reference region based Logan graphical analysis. Regionally averaged values of parametric results were compared with the BPND of corresponding regions from arterial input compartment modeling. Dynamic PET data were also pre-filtered using a 3D Gaussian smoothing of 5mm FWHM and the effect of the filtering on the correlation was investigated. In addition, the use of SUVR images was evaluated. The accuracy of several kinetic models were also assessed through simulations of time-activity curves based on clinical data for low and high binding adding different levels of statistical noise representing regions and individual voxels.

    RESULTS: The highest correlation was observed for pre-filtered reference Logan, with correction for individual reference region efflux rate constant k2' (R(2)=0.98), or using a cohort mean k2' (R(2)=0.97). Pre-processing filtered MRTM2, unfiltered SUVR over the scanning window 70-90min and unfiltered RPM also demonstrated high correlations with arterial input compartment modeling (MRTM2 R(2)=0.97, RPM R(2)=0.96 and SUVR R(2)=0.95) Poorest agreement was seen with MRTM without pre-filtering (R(2)=0.68).

    CONCLUSIONS: Parametric imaging allows for quantification without introducing bias due to selection of anatomical regions, and thus enables objective statistical voxel-based comparisons of tracer binding. Several parametric modeling approaches perform well, especially after Gaussian pre-filtering of the dynamic data. However, the semi-quantitative use of SUVR between 70 and 90min has comparable agreement with full kinetic modeling, thus supporting its use as a simplified method for quantitative assessment of tracer uptake.

  • 6. Höflich, Anna
    et al.
    Savli, Markus
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Moser, Ulrike
    Novak, Klaus
    Kasper, Siegfried
    Lanzenberger, Rupert
    Neuropsychiatric deep brain stimulation for translational neuroimaging2013In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 79, no 1, p. 30-41Article in journal (Refereed)
    Abstract [en]

    From a neuroimaging point of view, deep brain stimulation (DBS) in psychiatric disorders represents a unique source of information to probe results gained in functional, structural and molecular neuroimaging studies in vivo. However, the implementation has, up to now, been restricted by the heterogeneity of the data reported in DBS studies. The aim of the present study was therefore to provide a comprehensive and standardized database of currently used DBS targets in selected psychiatric disorders (obsessive–compulsive disorder (OCD), treatment-resistant depression (TRD), Gilles de la Tourette syndrome (GTS)) to enable topological comparisons between neuroimaging results and stimulation areas. A systematic literature research was performed and all peer-reviewed publications until the year 2012 were included. Literature research yielded a total of 84 peer-reviewed studies including about 296 psychiatric patients. The individual stimulation data of 37 of these studies meeting the inclusion criteria which included a total of 202 patients (63 OCD, 89 TRD, 50 GTS) was translated into MNI stereotactic space with respect to AC origin in order to identify key targets.

    The created database can be used to compare DBS target areas in MNI stereotactic coordinates with: 1) activation patterns in functional brain imaging (fMRI, phfMRI, PET, MET, EEG); 2) brain connectivity data (e.g., MR-based DTI/tractography, functional and effective connectivity); 3) quantitative molecular distribution data (e.g., neuroreceptor PET, post-mortem neuroreceptor mapping); 4) structural data (e.g., VBM for neuroplastic changes). Vice versa, the structural, functional and molecular data may provide a rationale to define new DBS targets and adjust/fine-tune currently used targets in DBS based on this overview in stereotactic coordinates. Furthermore, the availability of DBS data in stereotactic space may facilitate the investigation and interpretation of treatment effects and side effect of DBS by comparing these to neuroimaging results. The present study thus improves comparability between functional, structural and molecular data in standard stereotactic space gained in neuroimaging studies with surgical targets for DBS, which is among other possible implications of crucial importance for the definition of new targets for effective DBS.

  • 7.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Validation of parametric methods for [(11)C]PE2I positron emission tomography2013In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 74, p. 172-178Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I. The purpose of this study was to evaluate different methods for producing [(11)C]PE2I parametric images, showing binding potential (BPND) and relative delivery (R1) at the voxel level, using clinical data as well as simulations.

    METHODS

    Investigations were made in twelve subjects either with social anxiety disorder (n=6) or parkinsonian syndrome (n=6), each receiving an 80min dynamic PET scan. All subjects underwent a T1-weighted MRI scan which was co-registered to the PET images and used for definition of regions of interest using a probabilistic template (PVElab). Two basis function implementations (receptor parametric mapping: RPM, RPM2) of the simplified reference tissue model (SRTM) and three multilinear reference tissue models (MRTMo, MRTM and MRTM2) were used for computation of parametric BPND and R1 images. In addition, reference Logan and standard uptake value ratio (SUVr) were investigated. Evaluations of BPND and R1 images were performed using linear regression to compare the parametric methods to region-based analyses with SRTM and cerebellar gray matter as reference region. Accuracy and precision of each method were assessed by simulations.

    RESULTS

    Correlation and slope of linear regression between parametric and region-based BPND and R1 values in both striatum and extra-striatal regions were optimal for RPM (R(2)=0.99 for both BPND and R1; slopes 0.99 and 0.98 for BPND and R1, respectively, in striatum). In addition, accuracy and precision were best for RPM and RPM2.

    CONCLUSION

    The basis function methods provided more robust estimations of the parameters compared to the other models and performed best in simulations. RPM, a basis function implementation of SRTM, is the preferred method for voxel level analysis of [(11)C]PE2I PET studies.

  • 8.
    Kågedal, Matts
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cselenyi, Zsolt
    Nyberg, Svante
    Raboisson, Patrick
    Ståhle, Lars
    Stenkrona, Per
    Varnäs, Katarina
    Halldin, Christer
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066-Estimating occupancy in the absence of a reference region2013In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 82, p. 160-169Article in journal (Refereed)
    Abstract [en]

    AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [C-11]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived fro m each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

  • 9.
    Kågedal, Matts
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, SE-151 85 Södertälje, Sweden.
    Cselényi, Zsolt
    Nyberg, Svante
    AstraZeneca R&D, SE-151 85 Södertälje, Sweden.
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Raboisson, Patrick
    Stenkrona, Per
    Hooker, Andrew C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers2012In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 61, no 4, p. 849-856Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain.

    AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed.

    The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200nM. The density of the receptor binding sites was estimated to 800nM and 200nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.

  • 10.
    Kågedal, Matts
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Varnäs, Katarina
    Hooker, Andrew C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Extension of the simplified reference tissue model, to allow different non-specific concentrations in the brain region of interest and the reference region. Application to PET with the radioligand [11C]AZ10419369 displaced by AZD3783 at the serotonin 5HT1B receptor.In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572Article in journal (Other academic)
  • 11. Looi, Jefferey Chee Leong
    et al.
    Walterfang, Mark
    Styner, Martin
    Svensson, Leif
    Lindberg, Olof
    Karolinska institutet.
    Östberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Logopedi.
    Botes, Lisa
    Örndahl, Eeva
    Chua, Phyllis
    Kumar, Rajeev
    Velakoulis, Dennis
    Wahlund, Lars-Olof
    Shape analysis of the neostriatum in frontotemporal lobar degeneration, Alzheimer's disease, and controls2010In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 51, no 3, p. 970-986Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD), but not Alzheimer's disease, or healthy aging. We measured the neostriatum (caudate nucleus and putamen) volume in FTLD (n=34), in comparison with controls (n=27) and Alzheimer's disease (AD, n=19) subjects.

    Methods: Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intra-cranial volume was calculated via a stereological point counting technique and was used for scaling the shape analysis. The manual segmentation binaries were analyzed using UNC Shape Analysis tools (University of North Carolina) to perform comparisons among FTLD, AD, and controls for global shape, local p-value significance maps, and mean magnitude of shape displacement.

    Results: Shape analysis revealed that there was significant shape difference between FTLD, AD, and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. There was a lateralized difference in shape for the left caudate for FTLD compared to AD; non-specific global atrophy in AD compared to controls; while FTLD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits.

    Conclusions: Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with implications for frontostriatal and corticostriatal motoric circuits, in FTLD, AD, and controls.

  • 12.
    Nordenskjöld, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Simmons, Andrew
    Brooks, Samantha J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Intracranial volume estimated with commonly used methods could introduce bias in studies including brain volume measurements2013In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 83, p. 355-360Article in journal (Refereed)
    Abstract [en]

    In brain volumetric studies, intracranial volume (ICV) is often used as an estimate of pre-morbid brain size as well as to compensate for inter-subject variations in head size. However, if the estimated ICV is biased by for example gender or atrophy, it could introduce errors in study results. To evaluate how two commonly used methods for ICV estimation perform, computer assisted reference segmentations were created and evaluated. Segmentations were created for 399 MRI volumes from 75-year-old subjects, with 53 of these subjects having an additional scan and segmentation created at age 80. ICV estimates from Statistical Parametric Mapping (SPM, version 8) and Freesurfer (FS, version 5.1.0) were compared to the reference segmentations, and bias related to skull size (approximated with the segmentation measure), gender or atrophy were tested for. The possible ICV related effect on associations between normalized hippocampal volume and factors gender, education and cognition was evaluated by normalizing hippocampal volume with different ICV measures. Excellent agreement was seen for inter- (r=0.999) and intra- (r=0.999) operator reference segmentations. Both SPM and FS overestimated ICV. SPM showed bias associated with gender and atrophy while FS showed bias dependent on skull size. All methods showed good correlation between time points in the longitudinal data (reference: 0.998, SPM: 0.962, FS: 0.995). Hippocampal volume showed different associations with cognition and gender depending on which ICV measure was used for hippocampal volume normalization. These results show that the choice of method used for ICV estimation can bias results in studies including brain volume measurements.

  • 13.
    Peira, Nathalie
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden..
    Ziaei, Maryam
    Univ QLD, Sch Psychol, St Lucia, Qld 4072, Australia..
    Persson, Jonas
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden.;Karolinska Inst, Aging Res Ctr ARC, S-11330 Stockholm, Sweden.;Stockholm Univ, S-11330 Stockholm, Sweden..
    Age differences in brain systems supporting transient and sustained processes involved in prospective memory and working memory2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 125, p. 745-755Article in journal (Refereed)
    Abstract [en]

    In prospective memory (PM), an intention to act in response to an external event is formed, retained, and at a later stage, when the event occurs, the relevant action is performed. PM typically shows a decline in late adulthood, which might affect functions of daily living. The neural correlates of this decline are not well understood. Here, 15 young (6 female; age range = 23-30 years) and 16 older adults (5 female; age range = 64-74 years) were scanned with fMRI to examine age-related differences in brain activation associated with event-based PM using a task that facilitated the separation of transient and sustained components of PM. We show that older adults had reduced performance in conditions with high demands on prospective and working memory, while no age-difference was observed in low-demanding tasks. Across age groups, PM task performance activated separate sets of brain regions for transient and sustained responses. Age-differences in transient activation were found in fronto-striatal and MTL regions, with young adults showing more activation than older adults. Increased activation in young, compared to older adults, was also found for sustained PM activation in the IFG. These results provide new evidence that PM relies on dissociable transient and sustained cognitive processes, and that age-related deficits in PM can be explained by an inability to recruit PM-related brain networks in old age.

  • 14.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Spreng, R Nathan
    Turner, Gary
    Herlitz, Agneta
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Stening, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wahlund, Lars-Olof
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Söderlund, Hedvig
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sex differences in volume and structural covariance of the anterior and posterior hippocampus2014In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, no 99, p. 215-25Article in journal (Refereed)
    Abstract [en]

    Sex differences in episodic and spatial memory are frequently observed, suggesting that there may be sex-related structural differences in the hippocampus (HC). Earlier findings are inconsistent, possibly due to a known variability along the hippocampal longitudinal axis. Here, we assessed potential sex differences in hippocampal volume and structural covariance with the rest of the brain in young men and women (N=76), considering the anterior (aHC) and posterior (pHC) hippocampus separately. Women exhibited a larger pHC than men adjusted for brain size. Using partial least squares, we identified two significant patterns of structural covariance of the aHC and pHC. The first included brain areas that covaried positively and negatively in volume with both the aHC and pHC in men, but showed greater covariance with the aHC than pHC in women. The second pattern revealed distinct structural covariance of the aHC and pHC that showed a clear difference between men and women: in men the pHC showed reliable structural covariance with the medial and lateral parietal lobes and the prefrontal cortex, whereas in women the aHC showed reliable structural covariance with the anterior temporal lobe bilaterally. This pattern converges with resting state functional connectivity of the aHC and pHC and suggests that these hippocampal sections interact with different brain regions, consistent with a division of labor with regards to episodic and spatial memory. Our findings lend support to a division of the HC into an anterior and posterior part and identify sex as a potential moderating factor when investigating hippocampal structure and connectivity.

  • 15.
    Pissiota, Anna
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Takahashi, K
    Flaten, MA
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    The human startle response and activation of the pons.2001In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 13, no 6, p. S461-Article in journal (Refereed)
  • 16.
    Razifar, Pasha
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Axelsson, Jan
    Uppsala Imanet.
    Schneider, Harald
    Uppsala Imanet.
    Långström, Bengt
    Uppsala Imanet. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A new application of pre-normalized principal component analysis for improvement of image quality and clinical diagnosis in human brain PET studies - Clinical brain studies using [C-11]-GR205171, [C-11]-L-deuterium-deprenyl, [C-11]-5-hydroxy-L-tryptophan, [C-11]-L-DOPA and Pittsburgh Compound-B2006In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 33, no 2, p. 588-598Article in journal (Refereed)
    Abstract [en]

    Principal component analysis (PCA) is one of the most applied multivariate image analysis tool on dynamic Positron Emission Tomography (PET). Independent of used reconstruction methodologies, PET images contain correlation in-between pixels, correlations in-between frame and errors caused by the reconstruction algorithm including different corrections, which can affect the performance of the PCA. In this study, we have investigated a new approach of application of PCA on pre-normalized, dynamic human PET images. A range of different tracers have been used for this purpose to explore the performance of the new method as a way to improve detection and visualization of significant changes in tracer kinetics and to enhance the discrimination between pathological and healthy regions in the brain. We compare the new results with the results obtained using other methods. Images generated using the new approach contain more detailed anatomical information with higher quality, precision and visualization, compared with images generated using other methods.

  • 17. Rostami, Elham
    Mechanisms of blast induced brain injuries, experimental studies in rats.2011In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 54, no 1, p. 89-97Article in journal (Refereed)
  • 18.
    Shariatgorji, Mohammadreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Strittmatter, Nicole
    AstraZeneca, Drug Safety & Metab, Cambridge CB4 0WG, England..
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kallbäck, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alvarsson, Alexandra
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Zhang, Xiaoqun
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Vallianatou, Theodosia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svenningsson, Per
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, S-17176 Stockholm, Sweden..
    Goodwin, Richard J. A.
    AstraZeneca, Drug Safety & Metab, Cambridge CB4 0WG, England..
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 136, p. 129-138Article in journal (Refereed)
    Abstract [en]

    With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

  • 19. Spies, M
    et al.
    Hahn, A
    Kranz, G S
    Sladky, R
    Kaufmann, U
    Hummer, A
    Ganger, S
    Kraus, C
    Winkler, D
    Seiger, R
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Windischberger, C
    Kasper, S
    Lanzenberger, R
    Gender transition affects neural correlates of empathy: A resting state functional connectivity study with ultra high-field 7T MR imaging2016In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 138, p. 257-265Article in journal (Refereed)
    Abstract [en]

    Sex-steroid hormones have repeatedly been shown to influence empathy, which is in turn reflected in resting state functional connectivity (rsFC). Cross-sex hormone treatment in transgender individuals provides the opportunity to examine changes to rsFC over gender transition. We aimed to investigate whether sex-steroid hormones influence rsFC patterns related to unique aspects of empathy, namely emotion recognition and description as well as emotional contagion. RsFC data was acquired with 7Tesla magnetic resonance imaging in 24 male-to-female (MtF) and 33 female-to-male (FtM) transgender individuals before treatment, in addition to 33 male- and 44 female controls. Of the transgender participants, 15 MtF and 20 FtM were additionally assessed after four weeks and four months of treatment. Empathy scores were acquired at the same time-points. MtF differed at baseline from all other groups and assimilated over the course of gender transition in a rsFC network around the supramarginal gyrus, a region central to interpersonal emotion processing. While changes to sex-steroid hormones did not correlate with rsFC in this network, a sex hormone independent association between empathy scores and rsFC was found. Our results underline that 1) MtF transgender persons demonstrate unique rsFC patterns in a network related to empathy and 2) changes within this network over gender transition are likely related to changes in emotion recognition, -description, and -contagion, and are sex-steroid hormone independent.

  • 20.
    Syvänen, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Blomquist, Gunnar
    Sprycha, Margareta
    Höglund, A. Urban
    Roman, Magnus
    Eriksson, Olof
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET2006In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 32, no 3, p. 1134-1141Article in journal (Refereed)
    Abstract [en]

    Active efflux transporters in the blood-brain barrier lower the brain concentrations of many drug molecules and endogenous substances and thus affect their central action. The objective of this investigation was to study the dynamics of the entire inhibition process of the efflux transporter P-glycoprotein (P-gp), using positron emission tomography (PET). The P-gp marker [C-11]verapamil was administered to anesthetized rats as an i.v. bolus dose followed by graded infusions via a computerized pump system to obtain a steady-state concentration of [C-11]verapamil in brain. The P-gp modulator cyclosporin A (CsA) (3, 10 and 25 mg/kg) was administered as a short bolus injection 30 min after the start of the [C-11]verapamil infusion. The CsA pharmacokinetics was studied in whole blood in a parallel group of rats. The CsA blood concentrations were used as input to model P-gp inhibition. The inhibition of P-gp was observed as a rapid increase in brain concentrations of [C-11]verapamil, with a maximum after 5, 7.5 and 17.5 min for the respective doses. The respective increases in maximal [C-11]verapamil concentrations were 1.5, 2.5 and 4 times the baseline concentration. A model in which CsA inhibited P-gp by decreasing the transport of [C-11]verapamil out from the brain resulted in the best fit. Our data suggest that it is not the CsA concentration in blood, but rather the CsA concentration in an effect compartment, probably the endothelial cells of the blood-brain barrier that is responsible for the inhibition of P-gp.

  • 21.
    Syvänen, Stina
    et al.
    Leiden University.
    de Lange, Elizabeth C
    Tagawa, Yoshihiko
    Schenke, Maarten
    Molthoff, Carla F M
    Windhorst, Albert D
    Lammertsma, Adriaan A
    Voskuyl, Rob A
    Simultaneous in vivo measurements of receptor density and affinity using [11C]flumazenil and positron emission tomography: comparison of full saturation and steady state methods.2011In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 57, no 3, p. 928-37Article in journal (Refereed)
    Abstract [en]

    The binding of PET radiotracer [(11)C]flumazenil to the GABA(A) receptors is described by the receptor density (B(max)) and binding affinity (K(D)). The estimation of B(max) and K(D) is usually based on Scatchard analysis including at least two PET scans at steady state of various specific activities. Recently, a novel full saturation method to estimate both B(max) and K(D) was proposed, in which a saturating dose of flumazenil is given to cover a wide range of different receptor occupancies within a single scan. The aim of the present study was a direct comparison of steady state and full saturation methods for determining B(max) and K(D) of [(11)C]flumazenil in the same group of male Sprague-Dawley rats. Fourteen rats underwent 3 consecutive [(11)C]flumazenil scans of 30 min duration each. A tracer dose was injected at the start of the first scan. Prior to the second scan the tracer was mixed with 5, 20, 100 or 500 μg unlabelled (cold) flumazenil to cover a wide range of receptor occupancies during the scan. The third scan was performed during a constant intravenous infusion of unlabelled flumazenil, resulting in ~50% GABA(A) receptor occupancy. The first and third scans were part of the steady state method, whilst the second scan was performed according to the full saturation method. For both methods, B(max) and K(D) were then derived by compartmental modelling. Both methods yielded similar B(max) and K(D) estimates. The full saturation method yielded B(max) values of 37 ± 5.8 ng · mL(-1) and K(D) values of 7.6 ± 2.0 ng · mL(-1), whilst the steady state method yielded B(max) values of 33 ± 5.4 ng · mL(-1) and K(D) values of 7.1 ± 0.8 ng · mL(-1). The main advantage of the full saturation method is that B(max) and K(D) can be obtained from a single PET scan.

  • 22.
    Syvänen, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fang, Xiaotian T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hultqvist, Greta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Meier, Silvio R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    A bispecific Tribody PET radioligand for visualization of amyloid-beta protofibrils - a new concept for neuroimaging2017In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 148, p. 55-63Article in journal (Refereed)
    Abstract [en]

    Antibodies are highly specific for their target molecules, but their poor brain penetrance has restricted their use as PET ligands for imaging of targets within the CNS. The aim of this study was to develop an antibody-based radioligand, using the Tribody(TM) format, for PET imaging of soluble amyloid-beta (All) protofibrils, which are suggested to cause neurodegeneration in Alzheimer's disease. Antibodies, even when expressed in smaller engineered formats, are large molecules that do not enter the brain in sufficient amounts for imaging purposes. Hence, their transport across the blood-brain barrier (BBB) needs to be facilitated, for example through interaction with the transferrin receptor (TfR). Thus, a Fab fragment of the TfR antibody 8D3 was fused with two single chain variable fragments (scFv) of the A beta protofibril selective antibody mAb158. Five Tribody proteins (A1-A5) were generated with different linkers between the Fab-8D3 and scFv-158. All proteins bound to TfR and All protofibrils in vitro. Three of the proteins (A1-A3) were radiolabeled with iodine-125 and studied ex vivo in wild-type (wt) and transgenic mice overexpressing human All. The systemic pharmacokinetics were similar with half-lives in blood of around 9 h for all three ligands. Brain concentrations at 2 h were around 1% of the injected dose per gram brain tissue, which is similar to what is observed for small molecular radioligands and at least 10-fold higher than antibodies in general. At 72 h, transgenic mice showed higher concentrations of radioactivity in the brain than wt mice (12, 15- and 16-fold for Al, A2 and A3 respectively), except in the cerebellum, an area largely devoid of A beta pathology. A3 was then labelled with iodine-124 for in vivo positron emission tomography (PET) imaging. Brain concentrations were quantified in six different regions showing a clear distinction both quantitatively and visually between wt and transgenic mice and a good correlation with A beta pathology. We have thus produced a recombinant, bispecific protein, actively transported into the brain, for PET imaging within the CNS. In a longer perspective, this technique may enable imaging of other proteins involved in neurodegenerative diseases for which imaging agents are completely lacking today.

  • 23.
    Vallianatou, Theodosia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strittmatter, Nicole
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hamm, Gregory
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Pereira, Marcela
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Källback, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Svenningsson, Per
    Karolinska Inst, Ctr Mol Med, Dept Neurol & Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Goodwin, Richard J. A.
    AstraZeneca, IMED Biotech Unit, Pathol Sci Drug Safety & Metab, Cambridge, England.
    Andrén, Per E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    A mass spectrometry imaging approach for investigating how drug-drug interactions influence drug blood-brain barrier permeability2018In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 172, p. 808-816Article in journal (Refereed)
    Abstract [en]

    There is a high need to develop quantitative imaging methods capable of providing detailed brain localization information of several molecular species simultaneously. In addition, extensive information on the effect of the blood-brain barrier on the penetration, distribution and efficacy of neuroactive compounds is required. Thus, we have developed a mass spectrometry imaging method to visualize and quantify the brain distribution of drugs with varying blood-brain barrier permeability. With this approach, we were able to determine blood-brain barrier transport of different drugs and define the drug distribution in very small brain structures (e.g., choroid plexus) due to the high spatial resolution provided. Simultaneously, we investigated the effect of drug-drug interactions by inhibiting the membrane transporter multidrug resistance 1 protein. We propose that the described approach can serve as a valuable analytical tool during the development of neuroactive drugs, as it can provide physiologically relevant information often neglected by traditional imaging technologies.

  • 24. Ziaei, Maryam
    et al.
    Peira, Nathalie
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Persson, Jonas
    Brain systems underlying attentional control and emotional distraction during working memory encoding2014In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 87, p. 276-286Article in journal (Refereed)
    Abstract [en]

    Goal-directed behavior requires that cognitive operations can be protected from emotional distraction induced by task-irrelevant emotional stimuli. The brain processes involved in attending to relevant information while filtering out irrelevant information are still largely unknown. To investigate the neural and behavioral underpinnings of attending to task-relevant emotional stimuli while ignoring irrelevant stimuli, we used fMRI to assess brain responses during attentional instructed encoding within an emotional working memory (WM) paradigm. We showed that instructed attention to emotion during WM encoding resulted in enhanced performance, by means of increased memory performance and reduced reaction time, compared to passive viewing. A similar performance benefit was also demonstrated for recognition memory performance, although for positive pictures only. Functional MRI data revealed a network of regions involved in directed attention to emotional information for both positive and negative pictures that included medial and lateral prefrontal cortices, fusiform gyrus, insula, the parahippocampal gyrus, and the amygdala. Moreover, we demonstrate that regions in the striatum, and regions associated with the default-mode network were differentially activated for emotional distraction compared to neutral distraction. Activation in a sub-set of these regions was related to individual differences in WM and recognition memory performance, thus likely contributing to performing the task at an optimal level. The present results provide initial insights into the behavioral and neural consequences of instructed attention and emotional distraction during WM encoding.

  • 25.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Kragel, Philip A.
    Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA..
    Zielinski, David J.
    Duke Univ, Pratt Sch Engn, Durham, NC 27708 USA..
    Brady, Rachael
    Duke Univ, Pratt Sch Engn, Durham, NC 27708 USA..
    LaBar, Kevin S.
    Duke Univ, Ctr Cognit Neurosci, Durham, NC 27708 USA..
    Medial prefrontal pathways for the contextual regulation of extinguished fear in humans2015In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 122, p. 262-271Article in journal (Refereed)
    Abstract [en]

    The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS + in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS -. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.

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