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  • 1.
    Aarnio, Mikko
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wolf, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Peterson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Linnman, Clas
    Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.2017In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, p. 418-424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

  • 2.
    Appel, Lieuwe
    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.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lassen, Jorgen Buus
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET2014In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no 2, p. 251-261Article in journal (Refereed)
    Abstract [en]

    Tesofensine (TE) is a novel triple monoannine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [C-11]beta CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A signnoid E-max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.

  • 3.
    Appel, Lieuwe
    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.
    Geffen, Yona
    Heurling, Kerstin
    Eriksson, Catarina
    Antoni, Gunnar
    Kapur, Shitij
    BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans2009In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 19, no 12, p. 841-850Article in journal (Refereed)
    Abstract [en]

    BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.

  • 4.
    Appel, Lieuwe
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Use of C-11-PE2I PET in Differential Diagnosis of Parkinsonian Disorders2015In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, no 2, p. 234-242Article in journal (Refereed)
    Abstract [en]

    In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using I-123-FP-CIT (I-123-N-omega-fluoropropyl- 2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane, or I-123-ioflupane) SPECT and F-18-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic C-11-PE2I (N-(3-iodoprop-2E-enyl)-2 beta-carbomethoxy-3 beta-(4-methyl-phenyl) nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R-1]) at voxel level. This study aimed to evaluate the validity of C-11-PE2I PET against the dual-modality approach using I-123-FP-CIT SPECT and F-18-FDG PET.

    Methods: Sixteen patients with parkinsonian disorders had a dual examination with F-18-FDG PET and I-123-FP-CIT SPECT following clinical routines and additionally an experimental C-11-PE2I PET scan. Parametric BPND and R-1 images were generated using receptor parametric mapping with the cerebellum as a reference. T1-weighted MR imaging was used for automated definition of volumes of interest (VOI). The DAT VOIs included the basal ganglia, whereas the overall brain functional activity was examined using VOIs across the brain. BPND and R-1 values were compared with normalized I-123-FP-CIT and F-18-FDG uptake values, respectively, using Pearson correlations and regression analyses. In addition, 2 masked interpreters evaluated the images visually, in both the routine and the experimental datasets, for comparison of patient diagnoses.

    Results: Parametric C-11-PE2I BPND and R-1 images showed high consistency with I-123-FP-CIT SPECT and F-18-FDG PET images. Correlations between C-11-PE2I BPND and I-123-FP-CIT uptake ratios were 0.97 and 0.76 in the putamen and caudate nucleus, respectively. Regional C-11-PE2I R-1 values were moderately to highly correlated with normalized F-18-FDG values (range, 0.61-0.94). Visual assessment of DAT availability showed a high consistency between C-11-PE2I BPND and I-123-FP-CIT images, whereas the consistency was somewhat lower for appraisal of overall brain functional activity using I-123-FP-CIT and F-18-FDG images. Substantial differences were found between clinical diagnosis and both neuro-imaging diagnoses.

    Conclusion: A single, dynamic C-11-PE2I PET investigation is a powerful alternative to a dual examination with I-123-FP-CIT SPECT and F-18-FDG PET for differential diagnosis of parkinsonian disorders. A large-scale patient study is, however, needed to further investigate distinct pathologic patterns in overall brain functional activity for various parkinsonian disorders.

  • 5.
    Appel, Lieuwe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Michelgård, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Linnman, Claes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fernandez, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Langström, Bengt
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Altered NK1-receptor availability in patients with post traumatic stress disorder2009In: [Biological Psychiatry 2009, 65(8), Suppl. 1, 118S, no. 394], 2009, p. 118S-Conference paper (Refereed)
    Abstract [en]

    Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after one or more traumatic events causing extreme stress or grave physical harm. The neurokinin-1 (NK1) receptor is the primary receptor for substance P (SP); a neuropeptide suggested being involved in anxiety and depression. The present study investigated differences in NK1-receptor availability between PTSD patients and healthy controls, using positron emission tomography (PET). Methods: Eleven male refugee patients (age: 41±10) with DSM-IV defined PTSD and nine healthy male control subjects (age: 33±10) were investigated using the PET-tracer [11C]GR205171, supplied by Uppsala Imanet. GR205171 is a highly selective NK1-receptor antagonist. Scans were performed during 60 minutes in the resting state. Parametric images were generated using the graphical reference Patlak method assuming irreversible binding of [11C]GR205171 from 20-60 minutes and having cerebellum as reference region. Exploratory whole brain analyses were performed using the statistical parametric mapping (SPM2) software. Results: PTSD patients had lower [11C]GR205171 binding compared to controls, in frontal cortical clusters encompassing bilaterally insula and left Brodmann area 11, reflecting lower NK1-receptor availability. No areas were found in which PTSD patients had higher [11C]GR205171 binding. Conclusions: This is the first study reporting differences in NK1-receptor availability in PTSD patients relative to controls. A tentative conclusion is that PTSD patients have a down regulation of the NK1-receptor system, which could be either a risk factor or due to emotional trauma processing.

  • 6. Bergman, O.
    et al.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    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.
    Linnman, Claes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bani, M.
    Pich, E. M.
    Bettica, P.
    Henningsson, S.
    Manuck, S. B.
    Ferrell, R. E.
    Nikolova, Y. S.
    Hariri, A. R.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Westberg, L.
    Eriksson, E.
    Association between amygdala reactivity and a dopamine transporter gene polymorphism2014In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 4, p. e420-Article in journal (Refereed)
    Abstract [en]

    Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [O-15] water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

  • 7. Eng, W.
    et al.
    Atack, J. R.
    Bergström, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sanabria, S.
    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.
    Dawson, G. R.
    Sciberras, D.
    Hargreaves, R. J.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Burns, H. D.
    Occupancy of human brain GABA(A) receptors by the novel alpha 5 subtype-selective benzodiazepine site inverse agonist alpha 5IA as measured using [C-11]flumazenil PET imaging2010In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 59, no 7-8, p. 635-639Article in journal (Refereed)
    Abstract [en]

    GABA(A) receptor alpha 5-selective inverse agonists enhance cognitive performance in pre-clinical species. However, a key aspect of the clinical development of such compounds is the demonstration that in man such compounds are devoid of the anxiogenic-like activity associated with non-selective inverse agonists such as FG 7142. The triazolophthalazine alpha 5IA (3-(5-methylisoxazol-3-yl)-6-[(1-methyl-1,2,3-triazol-4-yl) methyloxy]-1,2,4-triazolo[3,4-a]phthalazine) is an alpha 5-selective inverse agonist which enhances cognitive performance in rodents and encouragingly in human Phase I Safety and Tolerability studies it was devoid of the anxiogenic-like activity associated with FG 7142. However, in order to appropriately interpret this latter observation, it was considered important to demonstrate that the absence of anxiogenic-like activity occurs at significant levels of receptor occupancy. Consequently, the occupancy of human brain GABAA receptors was measured using [C-11]flumazenil positron emission tomography in three healthy normal young male volunteers following a single oral dose of 2 mg alpha 5IA. One hour after dosing, mean occupancy levels were 53% and this fell to 16% by 8 h post-dose, with the plasma alpha 5IA concentration corresponding to 50% occupancy being 10 ng/mL. These data clearly show that an alpha 5-selective inverse agonist is not associated with anxiogenic-like side effects at doses that give 50% occupancy.

  • 8.
    Engman, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    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.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Age, sex and NK1 receptors in the human brain: A positron emission tomography study with [C-11]GR2051712012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 8, p. 562-568Article in journal (Refereed)
    Abstract [en]

    The substance P/neurokinin 1 (SP/NK1) system has been implicated in the processing of negative affect. Its role seems complex and findings from animal studies have not been easily translated to humans. Brain imaging studies on NK1 receptor distribution in humans have revealed an abundance of receptors in cortical, striatal and subcortical areas, including the amygdala. A reduction in NK1 receptors with increasing age has been reported in frontal, temporal, and parietal cortices, as well as in hippocampal areas. Also, a previous study suggests sex differences in cortical and subcortical areas, with women displaying fewer NK1 receptors. The present PET study explored NK1 receptor availability in men (n = 9) and women (n = 9) matched for age varying between 20 and 50 years using the highly specific NK1 receptor antagonist [11C]GR205171 and a reference tissue model with cerebellum as the reference region. Age by sex interactions in the amygdala and the temporal cortex reflected a lower NK1 receptor availability with increasing age in men, but not in women. A general age-related decline in NK1 receptor availability was evident in the frontal, temporal, and occipital cortices, as well as in the brainstem, caudate nucleus, and thalamus. Women had lower NK1 receptor availability in the thalamus. The observed pattern of NK1 receptor distribution in the brain might have functional significance for brain-related disorders showing age- and sex-related differences in prevalence.

  • 9.
    Fahlström, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lindskog, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Engström, Mathias
    GE Healthcare, Stockholm, Sweden..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Correlation between regional cerebral blood flow based on simultaneously acquired arterial spin labelling MRI and 15O-water-PET using zero-echo-time-based attenuation correction2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no S1, article id 362Article in journal (Other academic)
    Abstract [en]

    Objectives: Arterial spin labelling (ASL) MRI promises clinical value in several common neurological disorders. Its quantitative accuracy and reproducibility, however, need to be further validated, ideally using simultaneously acquired measurements with 15O-water-PET on an integrated PET-MR scanner. However, so far, few studies have attempted this and the inclusion of bone in MR-based attenuation correction for PET has thus far been a challenge, compromising the quantitative accuracy of PET-MR based 15O-water PET data. The aim of the present work was to assess the correlation of ASL- and 15O-water-PET based regional cerebral blood flow (rCBF) values based on simultaneously acquired data, using zero-echo-time (ZTE)-based attenuation correction, as well as to assess the reproducibility of ASL-based rCBF.

    Methods: Six subjects underwent 10 min PET scans after automated bolus injection of 400 MBq 15O-water (1 mL/s during 5 s followed by 35 mL saline at 2 mL/s) on a time-of-flight integrated PET-MR scanner (Signa PET-MR, GE Healthcare). Arterial blood radioactivity concentrations were monitored using continuous sampling from the radial artery (Swisstrace Twilite Two). Simultaneously, a 3D FSE pseudo-continuous ASL (3D pCASL) with a spiral read-out as supplied by the scanner manufacturer in the commercial software were acquired using an 8 channel head coil (Invivo Hi-Res Head Coil). In addition, 3D T1-w, ZTE and Dixon fat-water MRI were acquired. The ASL procedure was repeated after 2 h (patients remained in the scanner). Quantifiable ASL-based CBF maps were generated. PET images were reconstructed into 26 frames of increasing durations using time-of-flight OSEM (2 iterations, 28 subsets) and a 5 mm post-filter, with ZTE-based attenuation correction. Blood sampler data were corrected for delay and dispersion and 15O-water-based CBF maps were calculated using a basis function implementation of the single tissue compartment model including a fitted blood volume parameter. CBF maps were co-registered to each patient's T1-w image. 3D T1-w images were segmented and normalised to MNI space using SPM12, and anterior, middle and posterior flow territory volumes of interest (VOIs) were created from a standard template in MNI space and inversely transformed for each patient. In addition, a 45-VOI probabilistic template was applied using PVElab software. Correlations between PET- and ASL-based rCBF values were assessed using regression analysis, and reproducibility of ASL using a paired t-test.

    Results: Mean (CI) total brain grey matter CBF values were 67.2 (48.0-86.5) mL/min/100 g for 15O-water-PET and 65.5 (55.7-75.5) mL/min/100 g for ASL. Although correlation and agreement between 15O-water and ASL-based rCBF for individual VOIs in the 45-VOI template were generally poor, significant correlations were found on a grey matter flow territory basis, with R2 ranging from 0.70 in the anterior flow territory to 0.86 in the middle flow territory. rCBF values were significantly reduced between second and first ASL for all flow territories (p<0.01), with a mean decrease of 10%.

    Conclusion: A good correlation between regional flow territory CBF values based on ASL and 15O-water-PET was found, using ZTE-based attenuation correction for PET data which takes bone tissue into account. ASL values for regional flow territories may have potential applications in patients with dementia or cerebrovascular diseases affecting blood flow such as moya moya. The decrease of ASL-based rCBF values in the reproducibility study needs to be investigated further to assess whether this is a methodological issue or reflects a true decrease in rCBF. Research Support: Uppsala County Council

  • 10.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    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.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
    Linnman, Clas
    P.A.I.N. Group, Department of Anesthesia, Children's Hospital, Boston, MA, USA.
    Pissiota, Anna
    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.
    Bani, Massimo
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    M Pich, Emilio
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    Jacobsson, Eva
    Uppsala University Hospital and Quintiles AB Phase I Services, Uppsala, Sweden.
    Wahlsted, Kurt
    Uppsala University Hospital and Quintiles AB Phase I Services, Uppsala, Sweden.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder2012In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 37, no 10, p. 2222-2232Article in journal (Refereed)
    Abstract [en]

    The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments, Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern con-elated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.

  • 11.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
    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.
    Linnman, Clas
    P.A.I.N. Group, Department of Anesthesia, Children's Hospital, Boston, MA, USA.
    Bani, Massimo
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    M Pich, Emilio
    GlaxoSmithKline, Medicine Centre, Verona, Italy.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder2014In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 17, no 8, p. 1149-1157Article in journal (Refereed)
  • 12.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder2016In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 11, p. 1775-1783Article in journal (Refereed)
    Abstract [en]

    Abstract Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40 mg), the NK1R antagonist GR205171 (n=6; 5 mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

  • 13. Frick, Andreas
    et al.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Björkstrand, Johannes
    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.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlstedt, Kurt
    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 Surgical Sciences, Radiology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.2015In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 72, no 8, p. 794-802Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.

    OBJECTIVE: To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.

    DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014.

    MAIN OUTCOMES AND MEASURES: The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms.

    RESULTS: The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected).

    CONCLUSIONS AND RELEVANCE: Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

  • 14.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [(11)C]GR2051712015In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, article id e597Article in journal (Refereed)
    Abstract [en]

    The neurokinin-1 (NK1) receptor is abundantly expressed in the fear circuitry of the brain, including the amygdala, where it modulates stress and anxiety. Despite its proposed involvement in psychopathology, only a few studies of NK1 receptor availability in human subjects with anxiety disorders exist. Here, we compared NK1 receptor availability in patients with social anxiety disorder (SAD; n = 17) and healthy controls (n = 17) using positron emission tomography and the radiotracer [(11)C]GR205171. The Patlak Graphical plot using a cerebellar reference region was used to model the influx parameter, Ki measuring NK1 receptor availability. Voxel-wise statistical parametric mapping analyses revealed increased NK1 receptor availability specifically in the right amygdala in SAD patients relative to controls. Thus, we demonstrate that exaggerated social anxiety is related to enhanced NK1 receptor availability in the amygdala. This finding supports the contribution of NK1 receptors not only in animal models of stress and anxiety but also in humans with anxiety disorders.

  • 15.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Michelgård Palmquist, Åsa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fernandez, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Frans, Örjan
    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 Surgical Sciences, Radiology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 10, p. 1400-1407Article in journal (Refereed)
    Abstract [en]

    The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

  • 16. Furmark, Tomas
    et al.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Henningsson, Susanne
    Ahs, Fredrik
    Faria, Vanda
    Linnman, Clas
    Pissiota, Anna
    Frans, Orjan
    Bani, Massimo
    Bettica, Paolo
    Pich, Emilio Merlo
    Jacobsson, Eva
    Wahlstedt, Kurt
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Långström, Bengt
    Eriksson, Elias
    Fredrikson, Mats
    A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety2008In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49, p. 13066-74Article in journal (Refereed)
    Abstract [en]

    Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

  • 17.
    Furmark, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Henningsson, Susanne
    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.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Bani, Massimo
    Pich, Emilio Merlo
    Eriksson, Elias
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Genotype over-diagnosis in amygdala responsiveness: affective processing in social anxiety disorder2009In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 34, no 1, p. 30-40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although the amygdala is thought to be a crucial brain region for negative affect, neuroimaging studies do not always show enhanced amygdala response to aversive stimuli in patients with anxiety disorders. Serotonin (5-HT)-related genotypes may contribute to interindividual variability in amygdala responsiveness. The short (s) allele of the 5-HT transporter linked polymorphic region (5-HTTLPR) and the T variant of the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene have previously been associated with amygdala hyperresponsivity to negative faces in healthy controls. We investigated the influence of these polymorphisms on amygdala responsiveness to angry faces in patients with social anxiety disorder (SAD) compared with healthy controls. METHODS: We used positron emission tomography with oxygen 15-labelled water to assess regional cerebral blood flow in 34 patients with SAD and 18 controls who viewed photographs of angry and neutral faces presented in counterbalanced order. We genotyped all participants with respect to the 5-HTTLPR and TPH2 polymorphisms. RESULTS: Patients with SAD and controls had increased left amygdala activation in response to angry compared with neutral faces. Genotype but not diagnosis explained a significant portion of the variance in amygdala responsiveness, the response being more pronounced in carriers of s and/or T alleles. LIMITATIONS: Our analyses were limited owing to the small sample and the fact that we were unable to match participants on genotype before enrollment. In addition, other imaging techniques not used in our study may have revealed additional effects of emotional stimuli. CONCLUSION: Amygdala responsiveness to angry faces was more strongly related to serotonergic polymorphisms than to diagnosis of SAD. Emotion activation studies comparing amygdala excitability in patient and control groups could benefit from taking variation in 5-HT-related genes into account.

  • 18.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.2017In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 6, p. 263-274Article in journal (Refereed)
    Abstract [en]

    [11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

  • 19.
    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.
    Parametric methods for [11C]PE2I positron emission tomography2012In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 32, no S1, p. S155-S155Article in journal (Other academic)
  • 20.
    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.

  • 21.
    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.
    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.
    Effect of variations in cerebellum kinetics on robustness of [C-11]DASB parametric images2012In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 32, p. S180-S181Article in journal (Other academic)
  • 22.
    Jonasson, My
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Langaas, G.
    Uppsala University.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fazio, P.
    Karolinska Inst, Stockholm, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Varrone, A.
    Karolinska Inst, Stockholm, Sweden.
    Blood Flow Dependence of Early [C-11]PE2I and [F-18]FE-PE2I PET SUVR Measurements Used In the Differential Diagnosis of Parkinsonian Disorders2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S303-S304Article in journal (Other academic)
  • 23.
    Khalighi, Mohammad Mehdi
    et al.
    GE Healthcare, San Jose, CA USA..
    Engström, Mathias
    GE Healthcare, Stockholm, Sweden..
    Fan, Audrey
    Stanford Univ, Stanford, CA 94305 USA..
    Gulaka, Praveen
    Stanford Univ, Stanford, CA 94305 USA..
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Zaharchuk, Greg
    Stanford Univ, Stanford, CA 94305 USA..
    Validation of an image derived input function estimation method on PET/MR2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no S1, article id 661Article in journal (Other academic)
    Abstract [en]

    Objectives: The study objective was to validate a recently introduced non-invasive image derived input function (IDIF) estimation method with the gold standard arterial blood sampling.

    Methods: Six subjects (31-50 years old) were injected with 408±62 MBq of 15O-water simultaneously with the start of a 10 min PET scan on the SIGNA PET-MR (GE Healthcare, WI, Waukesha). During PET scanning, a sagittal vascular (inhance 3D velocity) MR series was used with the following parameters: TR=8.7 ms, TE=4.1 ms, FOV=24×21.6 cm, slice thickness=3 mm, 32 slices, velocity encoding=40, phase acceleration=2.0, and scan time=1:21 min. The PET list file was unlisted for every second and total true and scatter coincident events were plotted to identify tracer arrival into the brain arteries. Then, a short time frame over the arrival of the tracer to the cervical region was reconstructed to obtain a PET angiogram. The cervical arteries were then segmented using the MR vascular images and PETA images. Spill-over and spill- in artifacts were estimated using PETA images and the actual arterial volume was measured from the MR vascular images. The PET list file was unlisted and images were reconstructed for every 1 s for the first 30 s, every 3 s for the next 30 s, every 5 s for the 2nd minute, every 10 s for the 3rd and 4th minute and every 30 s for 5th to 10th minutes. The AIF was estimated by dividing total counts from the cervical arteries of each frame by the MR-based arterial volume. For each patient, blood samples were continuously drawn from the radial artery at the wrist using a peristaltic pump, and the tracer concentration in the arterial blood was measured using a Twilite two detector (Swisstrace) to estimate the AIF. In order to calculate the AIF at the brain arteries from these blood samples, the delay and dispersion of the arterial input function was corrected using standard PET-based methods. The CBF and distribution volume were calculated using both the IDIF method and the blood samples by minimizing the mean square of the error between the PET observations and model fit using the Nelder-Mead simplex algorithm in MATLAB (Mathworks, Wilmington, MA).

    Results: Figure 1 shows the (a) PETA and (b) MR vascular images for one of the patients. The PETA images clearly show the arteries and the extent of the spill-over. Figure 2 compares the AIF curve estimated by the proposed IDIF method and the AIF curve measured by the blood samples. The comparison shows excellent correspondence between the IDIF method and the gold standard blood sampling method with 9% and 11% difference for the 1st pass and the entire AIF, respectively. The IDIF captures the AIF peak correctly and has increased signal-to-noise ratio compared to the blood sampling method. The delay and the dispersion of the AIF curve is nearly identical between the two methods. The CBF over the whole brain was measured 29.5±8.7 and 27.0±14 ml/s/100g with the AIF measured by IDIF method and blood samples, respectively with a mean difference of 14% between the two methods. The volume distribution over the whole brain was measured 0.5±0.1 for both methods with a mean difference of 15% between them.

    Conclusion: As the results show, the proposed method is capable of determining a high fidelity IDIF from simultaneous PET/MRI data. Having a “blood-free” method that obviates the need for direct arterial sampling is of benefit to both investigators and their subjects, because of the high costs, inconvenience, and potential risks associated with arterial cannulation. It has applications beyond 15O-water PET, enabling pharmacokinetic modeling to be performed that is required for quantitative PET tracer studies. Research Support: GE Healthcare, Stanford University Lucas Center, Uppsala University.

  • 24.
    Laukka, Petri
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    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.
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Michelgård, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    In a nervous voice: Acoustic analysis and perception of anxiety in social phobics' speech2008In: Journal of nonverbal behavior, ISSN 0191-5886, E-ISSN 1573-3653, Vol. 32, no 4, p. 195-214Article in journal (Refereed)
    Abstract [en]

    This study investigated the effects of anxiety on nonverbal aspects of speech using data collected in the framework of a large study of social phobia treatment. The speech of social phobics (N = 71) was recorded during an anxiogenic public speaking task both before and after treatment. The speech samples were analyzed with respect to various acoustic parameters related to pitch, loudness, voice quality, and temporal apsects of speech. The samples were further content-masked by low-pass filtering (which obscures the linguistic content of the speech but preserves nonverbal affective cues) and subjected to listening tests. Results showed that a decrease in experienced state anxiety after treatment was accompanied by corresponding decreases in a) several acoustic parameters (i.e., mean and maximum voice pitch, high-frequency components in the energy spectrum, and proportion of silent pauses), and b) listeners' perceived level of nervousness. Both speakers' self-ratings of state anxiety and listeners' ratings of perceived nervousness were further correlated with similar acoustic parameters. The results complement earlier studies on vocal affect expression which have been conducted on posed, rather than authentic, emotional speech.

  • 25.
    Linnman, Clas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    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.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Söderlund, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Ventromedial prefrontal neurokinin 1 receptor availability is reduced in chronic pain2010In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 149, no 1, p. 64-70Article in journal (Refereed)
    Abstract [en]

    Neurokinin 1 (NK1) receptors are involved in pain and anxiety behaviors in animals, but little is known about central alterations in this receptor system in human pain. With positron emission tomography, using a [11]-Carbon labeled NK1 receptor antagonist, we demonstrate attenuated NK1 receptor availability in frontal, insular and cingulate cortex, as well as the hippocampus, amygdala and the periaqueductal gray area in patients with chronic pain. The reduced availability was most pronounced in the ventromedial prefrontal cortex (vmPFC), where attenuations correlated to measures of fear and avoidance of movement. Further, vmPFC NK1 levels also displayed opposing influences in patients as compared to controls on regional cerebral blood flow in the anterior cingulate. We conclude that the central NK1 receptor system is altered in human chronic pain. The results suggest that NK1 receptors in the vmPFC modulate motor inhibition, and contribute to fear and avoidance of movement.

  • 26.
    Linnman, Clas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    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.
    Söderlund, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Engler, Henry
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Långström, Bengt
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Chronic whiplash symptoms are related to altered regional cerebral blood flow in the resting state2009In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 13, no 1, p. 65-70Article in journal (Refereed)
    Abstract [en]

    The neural pathogenic mechanisms involved in mediating chronic pain and whiplash associated disorders (WAD) after rear impact car collisions are largely unknown. This study's first objective was to compare resting state regional cerebral blood flow (rCBF) by means of positron emission tomography with (15)O labelled water in 21 WAD patients with 18 healthy, pain-free controls. A second objective was to investigate the relations between brain areas with altered rCBF to pain experience, somatic symptoms, posttraumatic stress symptoms and personality traits in the patient group. Patients had heightened resting rCBF bilaterally in the posterior parahippocampal and the posterior cingulate gyri, in the right thalamus and the right medial prefrontal gyrus as well as lowered tempero-occipital blood flow compared with healthy controls. The altered rCBF in the patient group was correlated to neck disability ratings. We thus suggest an involvement of the posterior cingulate, parahippocampal and medial prefrontal gyri in WAD and speculate that alterations in the resting state are linked to an increased self-relevant evaluation of pain and stress.

  • 27.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Gaging, Johannes
    Uppsala Univ, Uppsala, Sweden..
    Lindskog, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tracer kinetic analysis of the SV2A ligand 11C-UCBA as a PET marker for synaptic density in humans2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no S1, article id 631Article in journal (Other academic)
    Abstract [en]

    Objectives: Quantitative imaging of the synaptic vesicle glycoprotein 2A (SV2A) with PET can be used as a measure of synaptic density in the human brain (Finnema et al, Science Tr Med 2016), changes of which occur in many neurodegenerative diseases. 11C-UCBA has previously been validated as an SV2A tracer in pigs (Estrada et al, Nucl Med Biol 2016), showing dose-dependent blocking and reversible binding. The aim of the present work was to evaluate tracer kinetic models and simplified methods for quantification of synaptic density using 11C-UCBA in humans.

    Methods: Eight subjects (6 epilepsy patients, 2 controls) underwent 90 min PET scans starting with injection of 5 MBq/kg 11C-UCBA on a time-of-flight integrated PET-MR scanner (Signa PET-MR, GE Healthcare). Arterial blood was withdrawn for measurements of whole blood and plasma concentrations and metabolite analysis. Images were reconstructed using zero-echo-time MR-based attenuation correction, accounting for bone attenuation. A probabilistic VOI template was defined on a T1-MRI image, acquired during the PET scan, and transferred to the dynamic PET images. A centrum semiovale VOI was drawn as potential reference tissue. Data were analysed using single-tissue (1T2k), two-tissue irreversible (2T3k) and reversible (2T4k) models, as well as the simplified reference tissue model (SRTM) and plasma- and reference-Logan methods, resulting in total distribution volume (VT) and binding potential (BPND) values, with binding potential both estimated directly and as distribution volume ratio to centrum semiovale (DVR). The optimal compartment model was determined using the Akaike information criterion (AIC). Standardized uptake value ratios (SUVR) at various time points were compared to modelling outcomes using regression analysis.

    Results: Plasma and brain kinetics of 11C-UCBA were slow, with peak activity in brain at 70-80 min. Parent fraction was approximately 50% at 90 min. Plasma-input data were best described using the 2T4k model, but this could often not provide robust VT or BPND values. Mean plasma-Logan VT was 24±17. Plasma-Logan DVR using centrum semiovale as reference tissue correlated well with 2T4k DVR (R2 0.94) for those regions where robust DVR values could be determined. Reference-Logan DVR showed good correlation with plasma-Logan DVR (R2 0.72). Plasma-Logan DVR-1 and SUVR-1 images are shown in Figure 1. SUVR for the 40-60 and 70-90 min intervals correlated well with reference-Logan DVR (R2 0.92 and 0.98).

    Conclusion: Slow kinetics of 11C-UCBA resulted in poor robustness of outcome parameters of reversible compartment models. However, reference-Logan DVR correlated well with plasma-Logan DVR. SUVR at 70-90 min p.i. correlated well with DVR and may be used as a simplified measure of synaptic density using 11C-UCBA. Research Support: Uppsala County Council

  • 28.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Phys..
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr..
    Lindskog, K.
    Uppsala Univ Hosp, Med Phys..
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr..
    Sprycha, M.
    Uppsala Univ Hosp, Med Imaging Ctr..
    Daging, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala Univ Hosp, Neurol..
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala Univ Hosp, Med Imaging Ctr..
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr..
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala Univ Hosp, Neurol..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala Univ Hosp, Med Imaging Ctr..
    Quantitative assessment of synaptic density using the SV2A ligand C-11-UCBA in humans2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 74-74Article in journal (Other academic)
  • 29.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Phys..
    Khalighi, M. M.
    GE Healthcare, Appl Sci Lab, Menlo Pk..
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr..
    Engstrom, M.
    GE Healthcare, Appl Sci Lab, Uppsala..
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging. Uppsala Univ Hosp, Med Imaging Ctr..
    Zaharchuk, G.
    Stanford Univ, Radiol..
    Validation of an image-derived input function method for O-15-water PET/MR brain scans2017In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 37, p. 80-81Article in journal (Other academic)
  • 30.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Widström, Charles
    Uppsala Univ Hosp, Uppsala, Sweden.
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Uppsala, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Uppsala, Sweden.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala Univ Hosp, Uppsala, Sweden.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Uppsala, Sweden.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Uppsala, Sweden.
    Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S409-S409Article in journal (Other academic)
  • 31.
    Michelgård, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Psychiatry, University hospital.
    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.
    Pissiota, Anna
    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.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Bergström, Mats
    Fredriksson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Symptom provocation in specific phobia affects the substance P neurokinin-1 receptor systems2007In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 61, no 8, p. 1002-1006Article in journal (Refereed)
    Abstract [en]

    Background: Animal studies demonstrate that stress and negative affect enhance the release of the neuropeptide substance P (SP), which binds to the neurokinin 1 (NK1) receptor. This positron emission tomography (PET) study evaluated how the activity in the SP-NK1 receptor system in the amygdala was affected by fear provocation in subjects with specific phobia. Methods: Sixteen adult women with DSM-IV-defined specific phobia for either snakes or spiders but not both viewed pictures of feared and non-feared animals while being PET-scanned for 60 min with the highly specific NK1 receptor antagonist [11C]GR205171 as the labeled PET tracer. Results: The uptake of the labeled NK1 receptor antagonist was significantly reduced in the right amygdala during phobic stimulation. In the left amygdala no significant differences were found between phobic and non-phobic conditions. There was a negative correlation in the right, but not left, amygdala between subjective anxiety ratings and NK1 tracer binding. Conclusions: Fear provocation affects the SP-NK1 receptor system in the right amygdala. This reflects reduced NK1 receptor availability during fear and could mirror an increased release of endogenous substance P.

  • 32.
    Peterson, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    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.
    Engler, Henry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Aarnio, Mikko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Langström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    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.
    PET-Scan Shows Peripherally Increased Neurokinin 1 Receptor Availability in Chronic Tennis Elbow: Visualizing Neurogenic Inflammation?2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, p. e75859-Article in journal (Refereed)
    Abstract [en]

    In response to pain, neurokinin 1 (NK1) receptor availability is altered in the central nervous system. The NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings. Ten subjects with chronic tennis elbow were therefore examined by positron emission tomography (PET) with the NK1 specific radioligand [C-11]GR205171 before and after treatment with graded exercise. The radioligand signal intensity was higher in the affected arm as compared with the unaffected arm, measured as differences between the arms in volume of voxels and signal intensity of this volume above a reference threshold set as 2.5 SD above mean signal intensity of the unaffected arm before treatment. In the eight subjects examined after treatment, pain ratings decreased in all subjects but signal intensity decreased in five and increased in three. In conclusion, NK1 receptors may be activated, or up-regulated in the peripheral, painful tissue of a chronic pain condition. This up-regulation does, however, have moderate correlation to pain ratings. The increased NK1 receptor availability is interpreted as part of ongoing neurogenic inflammation and may have correlation to the pathogenesis of chronic tennis elbow.

  • 33.
    Sousa, Joao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fang, Xiaotian T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Engström, M.
    GE Healthcare, Stockholm, Sweden.
    Khalighi, M.
    GE Healthcare, Stanford, CA USA.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Quantitative accuracy of 15O-water cerebral blood flow images based on penalized likelihood reconstruction2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S94-S95Article in journal (Other academic)
  • 34.
    Sousa, Joao M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Papadimitriou, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Nyholm, Dag
    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 Surgical Sciences, Radiology.
    Danfors, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Delso, G.
    GE Healthcare, Zurich, Switzerland..
    Wiesinger, F.
    GE Healthcare, Zurich, Switzerland..
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Validation of Zero-Echo Time PET-MR against stand-alone PET using dynamic dopamine transporter imaging2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, p. S79-S79Article in journal (Refereed)
  • 35.
    Sousa, João M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, PET Ctr, Uppsala, Sweden.
    Appel, Lieuwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr, Uppsala, Sweden.
    Engström, Mathias
    GE Healthcare, MR Appl Sci Lab, Waukesha, WI USA.
    Papadimitriou, Stergios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nyholm, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr, Uppsala, Sweden.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Med Imaging Ctr, Uppsala, Sweden.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala Univ Hosp, Dept Med Phys, Uppsala, Sweden.
    Evaluation of zero-echo-time attenuation correction for integrated PET/MR brain imaging-comparison to head atlas and 68Ge-transmission-based attenuation correction2018In: EJNMMI Physics, ISSN 2197-7364, E-ISSN 2191-219X, Vol. 5, no 20Article in journal (Refereed)
    Abstract [en]

    Background: MRI does not offer a direct method to obtain attenuation correction maps as its predecessors (stand-alone PET and PET/CT), and bone visualisation is particularly challenging. Recently, zero-echo-time (ZTE) was suggested for MR-based attenuation correction (AC). The aim of this work was to evaluate ZTE- and atlas-AC by comparison to 68Ge-transmission scan-based AC.

    Nine patients underwent brain PET/MR and stand-alone PET scanning using the dopamine transporter ligand 11C-PE2I. For each of them, two AC maps were obtained from the MR images: an atlas-based, obtained from T1-weighted LAVA-FLEX imaging with cortical bone inserted using a CT-based atlas, and an AC map generated from proton-density-weighted ZTE images. Stand-alone PET 68Ge-transmission AC map was used as gold standard. PET images were reconstructed using the three AC methods and standardised uptake value (SUV) values for the striatal, limbic and cortical regions, as well as the cerebellum (VOIs) were compared. SUV ratio (SUVR) values normalised for the cerebellum were also assessed. Bias, precision and agreement were calculated; statistical significance was evaluated using Wilcoxon matched-pairs signed-rank test.

    Results: Both ZTE- and atlas-AC showed a similar bias of 6–8% in SUV values across the regions. Correlation coefficients with 68Ge-AC were consistently high for ZTE-AC (r 0.99 for all regions), whereas they were lower for atlas-AC, varying from 0.99 in the striatum to 0.88 in the posterior cortical regions. SUVR showed an overall bias of 2.9 and 0.5% for atlas-AC and ZTE-AC, respectively. Correlations with 68Ge-AC were higher for ZTE-AC, varying from 0.99 in the striatum to 0.96 in the limbic regions, compared to atlas-AC (0.99 striatum to 0.77 posterior cortex).

    Conclusions: Absolute SUV values showed less variability for ZTE-AC than for atlas-AC when compared to 68Ge-AC, but bias was similar for both methods. This bias is largely caused by higher linear attenuation coefficients in atlas- and ZTE-AC image compared to 68Ge-images. For SUVR, bias was lower when using ZTE-AC than for atlas-AC. ZTE-AC shows to be a more robust technique than atlas-AC in terms of both intra- and inter-patient variability.

  • 36.
    Åhs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pissiota, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, Ulleråker, University Hospital.
    Michelgård, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    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.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Disentangling the web of fear: amygdala reactivity and functional connectivity in spider and snake phobia2009In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 172, no 2, p. 103-108Article in journal (Refereed)
    Abstract [en]

    The objective was to study effects of fear on brain activity, functional connectivity and brain-behavior relationships during symptom provocation in subjects with specific phobia. Positron emission tomography (PET) and (15)O water was used to measure regional cerebral blood flow (rCBF) in 16 women phobic of either snakes or spiders but not both. Subjects watched pictures of snakes and spiders serving either as phobic or fear-relevant, but non-phobic, control stimuli depending on phobia type. Presentation of phobic as compared with non-phobic cues was associated with increased activation of the right amygdala and cerebellum as well as the left visual cortex and circumscribed frontal areas. Activity decreased in the prefrontal, orbitofrontal and ventromedial cortices as well as in the primary somatosensory cortex and auditory cortices. Furthermore, amygdala activation correlated positively with the subjective experience of distress. Connectivity analyses of activity in the phobic state revealed increased functional couplings between voxels in the right amygdala and the periamygdaloid area, fusiform gyrus and motor cortex. During non-phobic stimulation, prefrontal activity correlated negatively with amygdala rCBF, suggesting a phobia-related functional decoupling. These results suggest that visually elicited phobic reactions activate object recognition areas and deactivate prefrontal areas involved in cognitive control over emotion-triggering areas like the amygdala, resulting in motor readiness to support fight or flight.

1 - 36 of 36
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