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  • 1.
    Ahs, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Davis, Caroline F
    Gorka, Adam X
    Hariri, Ahmad R
    Feature-based representations of emotional facial expressions in the human amygdala.2014In: Social cognitive and affective neuroscience, ISSN 1749-5024, Vol. 9, no 9, p. 1372-8Article in journal (Refereed)
    Abstract [en]

    The amygdala plays a central role in processing facial affect, responding to diverse expressions and features shared between expressions. Although speculation exists regarding the nature of relationships between expression- and feature-specific amygdala reactivity, this matter has not been fully explored. We used functional magnetic resonance imaging and principal component analysis (PCA) in a sample of 300 young adults, to investigate patterns related to expression- and feature-specific amygdala reactivity to faces displaying neutral, fearful, angry or surprised expressions. The PCA revealed a two-dimensional correlation structure that distinguished emotional categories. The first principal component separated neutral and surprised from fearful and angry expressions, whereas the second principal component separated neutral and angry from fearful and surprised expressions. This two-dimensional correlation structure of amygdala reactivity may represent specific feature-based cues conserved across discrete expressions. To delineate which feature-based cues characterized this pattern, face stimuli were averaged and then subtracted according to their principal component loadings. The first principal component corresponded to displacement of the eyebrows, whereas the second principal component corresponded to increased exposure of eye whites together with movement of the brow. Our results suggest a convergent representation of facial affect in the amygdala reflecting feature-based processing of discrete expressions.

  • 2. Appel, L
    et al.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Winqvist, I
    Michelgård, Åsa
    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.
    Bani, M
    Långström, B
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Enhanced amygdalar NK1-receptor availability in patients with social anxiety disorder.2007In: Biological Psychiatry, 2007, p. 147-Conference paper (Other academic)
  • 3.
    Bas-Hoogendam, Janna Marie
    et al.
    Department of Developmental and Educational Psychology, Leiden University, Institute of Psychology, Leiden, Netherlands; Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands; Leiden Institute for Brain and Cognition, Leiden, Netherlands.
    Groenewold, Nynke A
    Department of Psychiatry & Mental Health, University of Cape Town, Cape Town, South Africa.
    Aghajani, Moji
    Department of Psychiatry, Amsterdam UMC / VUMC, Amsterdam, Netherlands; Department of Research & Innovation, GGZ inGeest, Amsterdam, Netherlands.
    Freitag, Gabrielle F
    National Institute of Mental Health, Emotion and Development Branch, Bethesda, Maryland, USA.
    Harrewijn, Anita
    National Institute of Mental Health, Emotion and Development Branch, Bethesda, Maryland, USA.
    Hilbert, Kevin
    Department of Psychology, Humboldt‐Universität zu Berlin, Berlin, Germany.
    Jahanshad, Neda
    University of Southern California Keck School of Medicine, Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, California, USA.
    Thomopoulos, Sophia I
    University of Southern California Keck School of Medicine, Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, California, USA.
    Thompson, Paul M
    University of Southern California Keck School of Medicine, Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, California, USA.
    Veltman, Dick J
    Department of Psychiatry, Amsterdam UMC / VUMC, Amsterdam, Netherlands.
    Winkler, Anderson M
    National Institute of Mental Health, Emotion and Development Branch, Bethesda, Maryland, USA.
    Lueken, Ulrike
    Department of Psychology, Humboldt‐Universität zu Berlin, Berlin, Germany.
    Pine, Daniel S
    National Institute of Mental Health, Emotion and Development Branch, Bethesda, Maryland, USA.
    van der Wee, Nic J A
    Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands; Leiden Institute for Brain and Cognition, Leiden, Netherlands.
    Stein, Dan J
    Department of Psychiatry & Mental Health, University of Cape Town, Cape Town, South Africa; University of Cape Town, South African MRC Unit on Risk & Resilience in Mental Disorders, Cape Town, South Africa; University of Cape Town, Neuroscience Institute, Cape Town, South Africa.
    ENIGMA-Anxiety Working Group,
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    ENIGMA-anxiety working group: Rationale for and organization of large-scale neuroimaging studies of anxiety disorders2022In: Human Brain Mapping, ISSN 1065-9471, E-ISSN 1097-0193, Vol. 43, no 1, p. 83-112Article, review/survey (Refereed)
    Abstract [en]

    Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.

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    fulltext
  • 4.
    Bergman, O
    et al.
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Furmark, T
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Appel, L
    PET Centre, UppsalaUniversity Hospital and Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Linnman, C
    Department of Psychology, Uppsala University, Uppsala, Sweden; Departments of Anesthesiology and Radiology, Pain and AnalgesiaImaging Neuroscience (P.A.I.N.) Group, Boston Children’s Hospital, Center for Pain and the Brain, Harvard Medical School, Boston, MA, USA.
    Faria, V
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Bani, M
    GlaxoSmithKline, Medicine ResearchCentre, Verona, Italy.
    Pich, E M
    GlaxoSmithKline, Medicine ResearchCentre, Verona, Italy.
    Bettica, P
    GlaxoSmithKline, Medicine ResearchCentre, Verona, Italy.
    Henningsson, S
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Manuck, S B
    Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
    Ferrell, R E
    Human Genetics, Graduate School of Public Health, University of Pittsburgh,Pittsburgh, PA, USA.
    Nikolova, Y S
    Department of Physiology & Neuroscience and Duke Institute for Genome Science & Policy, Duke University, Durham, NC, USA. .
    Hariri, A R
    Department of Physiology & Neuroscience and Duke Institute for Genome Science & Policy, Duke University, Durham, NC, USA. .
    Fredrikson, M
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Westberg, L
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Eriksson, E
    Department of Pharmacology, University of Gothenburg, Gothenburg, Sweden.
    Association between amygdala reactivity and a dopamine transporter gene polymorphism2014In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 4, article id e420Article 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 [(15)O]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.

  • 5. 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, 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.

  • 6.
    Bjärtå, Anna
    et al.
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Bernhardsson, Jens
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Tjernberg, Michaela
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Sundin, Örjan
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Brief Intervention For Distress Related To Difficult And Traumatic Memories2019In: Libro de Actas, Granada: Asociación Española de Psicología Conductual , 2019, p. 268-Conference paper (Refereed)
    Abstract [en]

    Many people experience distress from memories of adverse events, so called trauma memories. Trauma interventions are often long and expensive and not easily accessible to, for example, people with sub clinical symptoms or refugees. Based on findings in neurocognitive basic research, a brief method to remedy symptoms related to trauma memories has been developed. The method consists of a one hour psychoeducative session in which individuals learn about distressing traumatic memories and how to handle them. The method aims to teach a way to deploy brain resources during reactivation of a memory in order to reduce fear and anxiety at reconsolidation. Nineteen individuals with difficult and distressing memories participated in a pilot trial. In a one hour session, participants were tought the method and basic knowledge about underlying brain functioning. They were instructed to practice the method during the following week. Pre, post (+1 week), and follow up (+ 5 weeks) measures of symptoms of posttraumatic stress, depression, and anxiety, showed significant decrease on all three scales with a persistant decrease at follow up. In general, results indicate that brief treatment methods can help results indicate that briefer methods can help people suffering from trauma memories.

  • 7.
    Björkstrand, Johannes
    et al.
    Lund university; Uppsala university.
    Agren, Thomas
    Uppsala University.
    Frick, Andreas
    Uppsala university.
    Hjorth, Olof
    Uppsala university.
    Furmark, Tomas
    Uppsala university.
    Fredrikson, Mats
    Uppsala university; Karolinska institutet.
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Decrease in amygdala activity during repeated exposure to spider images predicts avoidance behavior in spider fearful individuals.2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 292Article in journal (Refereed)
    Abstract [en]

    Spider phobia is characterized by exaggerated fear of situations where spiders could be present, resulting in avoidance of such situations and compromised quality of life. An important component in psychological treatment of spider phobia is exposure to phobic situations that reduces avoidance behaviors. At the neural level, amygdala responses to phobic material are elevated, but normalizes following exposure treatment. To what extent amygdala activity decreases during a session of repeated phobic stimulation, and whether activity decrease is related to subsequent avoidance is not well studied. We hypothesized reduced amygdala activity during the course of repeated exposure to spider pictures, and that the degree of reduction would predict subsequent avoidance of spider pictures. To test our hypothesis, functional magnetic resonance imaging was performed in 45 individuals with spider fear during repeated exposure to spider pictures. Results showed that repeated exposure to spider stimuli attenuated amygdala reactivity and individual differences in activity reductions predicted subsequent avoidance behavior to spider pictures in an incentive-conflict task, with larger attenuations predicting less avoidance. At 6-month follow up, initial reductions in amygdala activation still predicted avoidance. This result demonstrates that reduction in amygdala responses is related to clinically meaningful outcomes in human anxiety, and suggests that within-session reductions in amygdala responses could be an important mechanism explaining the clinical effects of exposure therapy.

    Download full text (pdf)
    fulltext
  • 8.
    Björkstrand, Johannes
    et al.
    Uppsala Universitet.
    Agren, Thomas
    Uppsala Universitet.
    Åhs, Fredrik
    Uppsala Universitet; Karolinska Institutet.
    Frick, Andreas
    Uppsala Universitet.
    Larsson, Elna-Marie
    Uppsala Universitet.
    Hjorth, Olof
    Uppsala Universitet.
    Furmark, Tomas
    Uppsala Universitet.
    Fredrikson, Mats
    Uppsala Universitet; Karolinska Institutet.
    Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior.2016In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 26, no 19, p. 2690-2695Article in journal (Refereed)
    Abstract [en]

    Memories become labile and malleable to modification when recalled [1]. Fear-conditioning experiments in both rodents and humans indicate that amygdala-localized short-term fear memories can be attenuated by disruption of their reconsolidation with extinction training soon after memory activation [2-7]. However, this may not be true for natural long-term fears. Studies in rodents indicate that although it is possible to disrupt the reconsolidation of older memories [8-11], they appear to be more resistant [1, 3, 9, 12, 13]. In humans, 1-week-old conditioned fear memories have been attenuated by behaviorally induced disruption of reconsolidation [14], but it remains to be seen whether this is possible for naturally occurring long-term fears and whether the underlying neural mechanisms are similar to those found in experimental fear-conditioning paradigms. Using functional brain imaging in individuals with a lifelong fear of spiders, we show that fear memory activation followed by repeated exposure to feared cues after 10 min, which disrupts reconsolidation, attenuates activity in the basolateral amygdala at re-exposure 24 hr later. In contrast, repeated exposure 6 hr after fear memory activation, which allows for reconsolidation, did not attenuate amygdala activity. Disrupted, but not undisrupted, reconsolidation facilitated approach behavior to feared cues, and approach behavior was inversely related to amygdala activity during re-exposure. We conclude that memory activation immediately preceding exposure attenuates the neural and behavioral expression of decades-old fear memories and that, similar to experimentally induced fear memories, the basolateral amygdala is crucially involved in this process.

  • 9.
    Björkstrand, Johannes
    et al.
    Uppsala Universitet.
    Agren, Thomas
    Uppsala Universitet.
    Åhs, Fredrik
    Uppsala Universitet; Karolinska Institutet.
    Frick, Andreas
    Uppsala Universitet; Karolinska Institutet.
    Larsson, Elna-Marie
    Uppsala Universitet.
    Hjorth, Olof
    Uppsala Universitet.
    Furmark, Tomas
    Uppsala Universitet.
    Fredrikson, Mats
    Uppsala Universitet; Karolinska Institutet.
    Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear2017In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 324, p. 125-129Article in journal (Refereed)
    Abstract [en]

    Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10min than the 6h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10min than the 6h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

  • 10.
    Björkstrand, Johannes
    et al.
    Uppsala Univ, Uppsala, Sweden.;Lund Univ, Lund, Sweden..
    Karlsson, Barry
    Uppsala Univ, Uppsala, Sweden..
    Rosen, Jorgen
    Uppsala Univ, Uppsala, Sweden..
    Olsson, Emil
    Lund Univ, Lund, Sweden..
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Fredrikson, Mats
    Uppsala Univ, Uppsala, Sweden.;Karolinska Inst, Solna, Sweden..
    Frick, Andreas
    Uppsala Univ, Uppsala, Sweden..
    High Unconditioned Stimulus Intensity Results in Stronger Threat Conditioning Than Low Intensity2020In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 87, no 9, p. S181-S181Article in journal (Refereed)
  • 11.
    Björkstrand, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Psychology, Lund University, Allhelgona Kyrkogata 14M, 223 50, Lund, Sweden.
    Ågren, Thomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Hjorth, Olof
    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.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 171 77, Stockholm, Sweden.
    Åhs, Fredrik
    Department of Psychology and Social Work, Mid Sweden University, Kunskapens väg 1, Östersund, Sweden.
    Decrease in amygdala activity during repeated exposure to spider images predicts avoidance behavior in spider fearful individuals2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 292Article in journal (Refereed)
    Abstract [en]

    Spider phobia is characterized by exaggerated fear of situations where spiders could be present, resulting in avoidance of such situations and compromised quality of life. An important component in psychological treatment of spider phobia is exposure to phobic situations that reduces avoidance behaviors. At the neural level, amygdala responses to phobic material are elevated, but normalizes following exposure treatment. To what extent amygdala activity decreases during a session of repeated phobic stimulation, and whether activity decrease is related to subsequent avoidance is not well studied. We hypothesized reduced amygdala activity during the course of repeated exposure to spider pictures, and that the degree of reduction would predict subsequent avoidance of spider pictures. To test our hypothesis, functional magnetic resonance imaging was performed in 45 individuals with spider fear during repeated exposure to spider pictures. Results showed that repeated exposure to spider stimuli attenuated amygdala reactivity and individual differences in activity reductions predicted subsequent avoidance behavior to spider pictures in an incentive-conflict task, with larger attenuations predicting less avoidance. At 6-month follow up, initial reductions in amygdala activation still predicted avoidance. This result demonstrates that reduction in amygdala responses is related to clinically meaningful outcomes in human anxiety, and suggests that within-session reductions in amygdala responses could be an important mechanism explaining the clinical effects of exposure therapy.

    Download full text (pdf)
    fulltext
  • 12.
    Björkstrand, Johannes
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Ågren, Thomas
    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 Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 171 77, Stockholm, Sweden.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 171 77, Stockholm, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Hjorth, Olof
    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.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 171 77, Stockholm, Sweden.
    Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear2017In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 324, p. 125-129Article in journal (Refereed)
    Abstract [en]

    Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10 min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6 h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10 min than the 6 h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10 min than the 6 h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

  • 13. Bruin, Willem B.
    et al.
    Zhutovsky, Paul
    van Wingen, Guido A.
    Bas-Hoogendam, Janna Marie
    Groenewold, Nynke A.
    Hilbert, Kevin
    Winkler, Anderson M.
    Zugman, Andre
    Agosta, Federica
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Andreescu, Carmen
    Antonacci, Chase
    Asami, Takeshi
    Assaf, Michal
    Barber, Jacques P.
    Bauer, Jochen
    Bavdekar, Shreya Y.
    Beesdo-Baum, Katja
    Benedetti, Francesco
    Bernstein, Rachel
    Björkstrand, Johannes
    Blair, Robert J.
    Blair, Karina S.
    Blanco-Hinojo, Laura
    Böhnlein, Joscha
    Brambilla, Paolo
    Bressan, Rodrigo A.
    Breuer, Fabian
    Cano, Marta
    Canu, Elisa
    Cardinale, Elise M.
    Cardoner, Narcís
    Cividini, Camilla
    Cremers, Henk
    Dannlowski, Udo
    Diefenbach, Gretchen J.
    Domschke, Katharina
    Doruyter, Alexander G. G.
    Dresler, Thomas
    Erhardt, Angelika
    Filippi, Massimo
    Fonzo, Gregory A.
    Freitag, Gabrielle F.
    Furmark, Tomas
    Ge, Tian
    Gerber, Andrew J.
    Gosnell, Savannah N.
    Grabe, Hans J.
    Grotegerd, Dominik
    Gur, Ruben C.
    Gur, Raquel E.
    Hamm, Alfons O.
    Han, Laura K. M.
    Harper, Jennifer C.
    Harrewijn, Anita
    Heeren, Alexandre
    Hofmann, David
    Jackowski, Andrea P.
    Jahanshad, Neda
    Jett, Laura
    Kaczkurkin, Antonia N.
    Khosravi, Parmis
    Kingsley, Ellen N.
    Kircher, Tilo
    Kostic, Milutin
    Larsen, Bart
    Lee, Sang-Hyuk
    Leehr, Elisabeth J.
    Leibenluft, Ellen
    Lochner, Christine
    Lui, Su
    Maggioni, Eleonora
    Manfro, Gisele G.
    Månsson, Kristoffer N. T.
    Marino, Claire E.
    Meeten, Frances
    Milrod, Barbara
    Jovanovic, Ana Munjiza
    Mwangi, Benson
    Myers, Michael J.
    Neufang, Susanne
    Nielsen, Jared A.
    Ohrmann, Patricia A.
    Ottaviani, Cristina
    Paulus, Martin P.
    Perino, Michael T.
    Phan, K. Luan
    Poletti, Sara
    Porta-Casteràs, Daniel
    Pujol, Jesus
    Reinecke, Andrea
    Ringlein, Grace V.
    Rjabtsenkov, Pavel
    Roelofs, Karin
    Salas, Ramiro
    Salum, Giovanni A.
    Satterthwaite, Theodore D.
    Schrammen, Elisabeth
    Sindermann, Lisa
    Smoller, Jordan W.
    Soares, Jair C.
    Stark, Rudolf
    Stein, Frederike
    Straube, Thomas
    Straube, Benjamin
    Strawn, Jeffrey R.
    Suarez-Jimenez, Benjamin
    Sylvester, Chad M.
    Talati, Ardesheer
    Thomopoulos, Sophia I.
    Tükel, Raşit
    van Nieuwenhuizen, Helena
    Werwath, Kathryn
    Wittfeld, Katharina
    Wright, Barry
    Wu, Mon-Ju
    Yang, Yunbo
    Zilverstand, Anna
    Zwanzger, Peter
    Blackford, Jennifer U.
    Avery, Suzanne N.
    Clauss, Jacqueline A.
    Lueken, Ulrike
    Thompson, Paul M.
    Pine, Daniel S.
    Stein, Dan J.
    van der Wee, Nic J. A.
    Veltman, Dick J.
    Aghajani, Moji
    Brain-based classification of youth with anxiety disorders: transdiagnostic examinations within the ENIGMA-Anxiety database using machine learning2024In: Nature Mental Health, ISSN 2731-6076, Vol. 2, no 1, p. 104-118Article in journal (Refereed)
    Abstract [en]

    Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we built and validated supervised neuroanatomical machine learning models for individual-level inferences, using a case–control design and the largest known neuroimaging database on youth anxiety disorders: the ENIGMA-Anxiety Consortium (N = 3,343; age = 10–25 years; global sites = 32). Modest, yet robust, brain-based classifications were achieved for specific anxiety disorders (panic disorder), but also transdiagnostically for all anxiety disorders when patients were subgrouped according to their sex, medication status and symptom severity (area under the receiver operating characteristic curve, 0.59–0.63). Classifications were driven by neuroanatomical features (cortical thickness, cortical surface area and subcortical volumes) in fronto-striato-limbic and temporoparietal regions. This benchmark study within a large, heterogeneous and multisite sample of youth with anxiety disorders reveals that only modest classification performances can be realistically achieved with machine learning using neuroanatomical data.

  • 14. Clason van de Leur, J.
    et al.
    Johansson, F.
    McCracken, L. M.
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Brodda Jansen, G.
    Buhrman, M.
    Mediators during a Multimodal intervention for stress-induced exhaustion disorder2024In: Cognitive Behaviour Therapy, ISSN 1650-6073, E-ISSN 1651-2316, Vol. 53, no 3, p. 235-253Article in journal (Refereed)
    Abstract [en]

    Our understanding of the underlying psychological processes of development, maintenance, and treatments for stress-induced exhaustion disorder (ED) remains limited. Therefore, the current study aimed to explore whether sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility mediate change in exhaustion symptoms during a Multimodal intervention for ED based on Cognitive behavioral therapy principles. Participants (N = 913) were assessed at three time points, and mediation was explored using a two-criteria analytical model with linear mixed-effects models (criterion one) and random intercepts cross-lagged panel modeling (criterion 2). Criterion one for mediation was successfully met, as the findings indicated significant associations between time in treatment, with all suggested mediators, and exhaustion symptoms (significant ab-products). However, criterion two was not satisfied as changes in the mediators did not precede changes in exhaustion symptoms. Therefore, mediation could not be established. Instead, changes in the suggested mediators appeared to result from changes in exhaustion symptoms. Consequently, sleep concerns, pathological worry, perfectionistic concerns, and psychological flexibility appear to improve in conjunction with exhaustion symptoms during treatment, where improvement in exhaustion is indicated as the main driving factor, based on this exploratory analysis. The implications of these findings are contextualized within a broader framework of process-based therapy. 

  • 15. Clason van de Leur, Jakob
    et al.
    Johansson, Fred
    McCracken, Lance M
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Brodda Jansen, Gunilla
    Buhrman, Monica
    Predictors and sub-groups in the treatment of stress-induced exhaustion disorder2023In: Cognitive Behaviour Therapy, ISSN 1650-6073, E-ISSN 1651-2316, Vol. 52, no 4, p. 397-418Article in journal (Refereed)
    Abstract [en]

    Little is known about psychological interventions for stress-induced Exhaustion disorder (ED), and there is a need for more research to improve the outcomes obtained in treatments. The present study examines predictors of improvement, including sub-group responses, in a large sample of ED patients receiving a Multimodal intervention (MMI) based on Cognitive Behavior Therapy (N = 915). In step one, available variables were explored separately as predictors of improvement in ED symptoms. In step two, sub-groups were explored through Latent Class Analysis to reduce the heterogeneity observed in the larger group and to investigate whether combining the variables from step one predicted symptom improvement. Younger age, no previous sick leave due to ED, and scoring high on anxiety, depression, insomnia, perfectionism, and treatment credibility emerged as separate predictors of improvement. In the sub-group analyses, a sub-group including participants who were single and had a lower income showed less improvement. Overall, people with ED participating in MMI report symptom improvement regardless of characteristics before treatment. However, the present findings do have the potential to inform future treatments for ED, as they highlight perfectionism as a predictor of improvement and the importance of assessing treatment credibility during treatment.

  • 16. Costache, Mădălina Elena
    et al.
    Frick, Andreas
    Månsson, Kristoffer
    Engman, Jonas
    Faria, Vanda
    Hjorth, Olof
    Hoppe, Johanna M
    Gingnell, Malin
    Frans, Örjan
    Björkstrand, Johannes
    Rosén, Jörgen
    Alaie, Iman
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Linnman, Clas
    Wahlstedt, Kurt
    Tillfors, Maria
    Marteinsdottir, Ina
    Fredrikson, Mats
    Furmark, Tomas
    Higher- and lower-order personality traits and cluster subtypes in social anxiety disorder.2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 4, article id e0232187Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.

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  • 17.
    Costache, Mădălina Elena
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Månsson, Kristoffer
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany; Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, United Kingdom; Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
    Engman, Jonas
    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. Center for Pain and The Brain, Department of Anesthesiology, Harvard Medical School, Boston Children’s Hospital, Perioperative and Pain Medicine, Boston, MA, United States of America; Department of Otorhinolaryngology, Smell & Taste Clinic, TU Dresden, Dresden, Germany.
    Hjorth, Olof
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Hoppe, Johanna M.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Frans, Örjan
    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. Department of Psychology, Lund University, Lund, Sweden.
    Rosén, Jörgen
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Åhs, Fredrik
    Department of Psychology and Social Work, Mid Sweden University, Östersund, Sweden.
    Linnman, Clas
    Harvard Med Sch, Spaulding Rehabil Hosp, Boston, MA 02115 USA.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Tillfors, Maria
    Department of Social and Psychological Studies, Karlstad University, Karlstad, Sweden .
    Marteinsdottir, Ina
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden .
    Fredrikson, Mats
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Higher- and lower-order personality traits and cluster subtypes in social anxiety disorder2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 4, article id e0232187Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) can come in different forms, presenting problems for diagnostic classification. Here, we examined personality traits in a large sample of patients (N = 265) diagnosed with SAD in comparison to healthy controls (N = 164) by use of the Revised NEO Personality Inventory (NEO-PI-R) and Karolinska Scales of Personality (KSP). In addition, we identified subtypes of SAD based on cluster analysis of the NEO-PI-R Big Five personality dimensions. Significant group differences in personality traits between patients and controls were noted on all Big Five dimensions except agreeableness. Group differences were further noted on most lower-order facets of NEO-PI-R, and nearly all KSP variables. A logistic regression analysis showed, however, that only neuroticism and extraversion remained significant independent predictors of patient/control group when controlling for the effects of the other Big Five dimensions. Also, only neuroticism and extraversion yielded large effect sizes when SAD patients were compared to Swedish normative data for the NEO-PI-R. A two-step cluster analysis resulted in three separate clusters labelled Prototypical (33%), Introvert-Conscientious (29%), and Instable-Open (38%) SAD. Individuals in the Prototypical cluster deviated most on the Big Five dimensions and they were at the most severe end in profile analyses of social anxiety, self-rated fear during public speaking, trait anxiety, and anxiety-related KSP variables. While additional studies are needed to determine if personality subtypes in SAD differ in etiological and treatment-related factors, the present results demonstrate considerable personality heterogeneity in socially anxious individuals, further underscoring that SAD is a multidimensional disorder.

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  • 18.
    Danfors, Torsten
    et al.
    Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden; Section of Nuclear Medicine and PET, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Appel, Lieuwe
    Section of Nuclear Medicine and PET, Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Sweden.
    Linnman, Clas
    Department of Psychology, Uppsala University, Uppsala, Sweden; P.A.I.N. group, McLean Hospital, Harvard Medical School, Boston, MA, USA.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Kumlien, Eva
    Department of Neuroscience, Neurology, Uppsala University, Uppsala, Sweden.
    Increased neurokinin-1 receptor availability in temporal lobe epilepsy: a positron emission tomography study using [(11)C]GR2051712011In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 97, no 1-2, p. 183-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Activation of the neurokinin-1 (NK1) receptor by neuropeptide substance P (SP) induces and maintains epileptic activity in various experimental models of epilepsy. The primary objective of this study was to investigate whether neurobiological changes linked to NK1-SP receptor system are associated with hyperexcitability in patients with temporal lobe epilepsy (TLE). A secondary objective was to investigate the relationship between seizure frequency and NK1 receptor availability.

    METHODS: A positron emission tomography study was conducted with the selective NK1 receptor antagonist [(11)C]GR205171 in nine patients with TLE and 18 healthy control participants. Parametric PET images were generated using the Patlak graphical method, with cerebellum as reference region. Data analyses including group comparisons were performed using statistical parametric mapping.

    RESULTS: Patients with TLE showed increased NK1 receptor availability in both hemispheres with the most pronounced increase in anterior cingulate gyrus ipsilateral to seizure onset. A positive correlation between NK1 receptor availability and seizure frequency was observed in the medial temporal lobe and in the lentiform nucleus ipsilateral to the seizure onset.

    CONCLUSION: Our results suggest that there is an intrinsic network using the NK1-SP receptor system for synaptic transmission and epileptiform activity in TLE.

  • 19. Dunsmoor, Joseph E
    et al.
    Åhs, Fredrik
    Labar, Kevin S
    Neurocognitive mechanisms of fear conditioning and vulnerability to anxiety2011In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 5, article id 35Article in journal (Refereed)
  • 20. Dunsmoor, Joseph E
    et al.
    Åhs, Fredrik
    Zielinski, David J
    LaBar, Kevin S
    Extinction in multiple virtual reality contexts diminishes fear reinstatement in humans2014In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 113, p. 157-164Article in journal (Refereed)
    Abstract [en]

    Although conditioned fear can be effectively extinguished by unreinforced exposure to a threat cue, fear responses tend to return when the cue is encountered some time after extinction (spontaneous recovery), in a novel environment (renewal), or following presentation of an aversive stimulus (reinstatement). As extinction represents a context-dependent form of new learning, one possible strategy to circumvent the return of fear is to conduct extinction across several environments. Here, we tested the effectiveness of multiple context extinction in a two-day fear conditioning experiment using 3-D virtual reality technology to create immersive, ecologically-valid context changes. Fear-potentiated startle served as the dependent measure. All three experimental groups initially acquired fear in a single context. A multiple extinction group then underwent extinction in three contexts, while a second group underwent extinction in the acquisition context and a third group underwent extinction in a single different context. All groups returned 24h later to test for return of fear in the extinction context (spontaneous recovery) and a novel context (renewal and reinstatement/test). Extinction in multiple contexts attenuated reinstatement of fear but did not reduce spontaneous recovery. Results from fear renewal were tendential. Our findings suggest that multi-context extinction can reduce fear relapse following an aversive event--an event that often induces return of fear in real-world settings--and provides empirical support for conducting exposure-based clinical treatments across a variety of environments.

  • 21.
    Engman, Jonas
    et al.
    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.
    Appel, Lieuwe
    Åhs, Fredrik
    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 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
    Bettica, Paolo
    Pich, Emilio Merlo
    Jacobsson, Eva
    Wahlstedt, Kurt
    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.
    Neural Correlates of Anxiety States in Patients with Social Anxiety Disorder2011In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 69, p. 70S-70SArticle in journal (Other academic)
    Abstract [en]

    Background: In social anxiety disorder (SAD), the fear of being negatively evaluated by others can restrict individual everyday life, due to the anxiety caused by social interactions. How this anxiety is processed in the brain is only partly understood. We aimed to examine the correlations between subjective anxiety states and brain activity in a large sample of SAD patients, during an anxiety-provoking task.

    Methods: Data were merged from three randomized clinical PET-trials investigating regional cerebral blood flow (rCBF) during a public speaking task pre- and post treatment (SSRI n = 35, placebo n = 37). All participants met diagnostical criteria for SAD. rCBF was assessed with [15O]-labeled water and state anxiety was measured using the Spielberger state anxiety scale (STAI-S). These measures where then correlated using a covariate of interest approach in Statistical Parametric Mapping (SPM2).

    Results: rCBF and STAI-S scores correlated positively in the left parahippocampal gyrus and amygdala, as well as in the right premotor cortex (area 6). Negative correlations were observed in the left superior frontal gyrus, thalamus, and the right parahippocampal gyrus. Negative correlations were also found bilaterally in the cerebellum.

    Conclusions: The correlations between clinical anxiety states and brain activity were noted in areas previously demonstrated to be involved in emotional regulation and motor preparedness.

  • 22.
    Engman, Jonas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Center for Cognitive Neuroscience, Duke University, Durham, NC, USA.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Linnman, Clas
    P.A.I.N. group, McLean Hospital/Harvard Medical School, Belmont, MA, USA.
    Pissiota, Anna
    Department of Neuroscience, Psychiatry, Uppsala University, Uppsala, Sweden.
    Appel, Lieuwe
    PET Centre, Department of Medical Imaging, Uppsala University Hospital, Sweden; Section of Nuclear Medicine and PET, Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Sweden.
    Frans, Örjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Långström, Bengt
    Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Age, sex and NK1 receptors in the human brain -- a positron emission tomography study with [¹¹C]GR2051712012In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 22, no 8, p. 562-8Article 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 50years 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.

  • 23. Fares-Otero, N. E.
    et al.
    Sharp, T. H.
    Balle, S. R.
    Quaatz, S. M.
    Vieta, E.
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Allgaier, A. -K
    Arévalo, A.
    Bachem, R.
    Belete, H.
    Mossie, T. B.
    Berzengi, A.
    Capraz, N.
    Ceylan, D.
    Dukes, D.
    Essadek, A.
    Iqbal, N.
    Jobson, L.
    Levy-Gigi, E.
    Lüönd, A.
    Martin-Soelch, C.
    Michael, T.
    Oe, M.
    Olff, M.
    Örnkloo, Helena
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Prakash, K.
    Ramakrishnan, Muniarajan
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Raghavan, V.
    Şar, V.
    Seedat, S.
    Spies, G.
    SusilKumar, V.
    Wadji, D. L.
    Wamser-Nanney, R.
    Haim-Nachum, S.
    Schnyder, U.
    Sopp, M. R.
    Pfaltz, Monique C.
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Halligan, S. L.
    Social support and (complex) posttraumatic stress symptom severity: does gender matter?2024In: European Journal of Psychotraumatology, ISSN 2000-8198, E-ISSN 2000-8066, Vol. 15, no 1, article id 2398921Article in journal (Refereed)
    Abstract [en]

    Background: Perceived social support is an established predictor of post-traumatic stress disorder (PTSD) after exposure to a traumatic event. Gender is an important factor that could differentiate responses to social support, yet this has been little explored. Symptoms of complex PTSD are also common following trauma but have been under-researched in this context. Large scale studies with culturally diverse samples are particularly lacking.Objectives: In a multi-country sample, we examined: (a) gender differences in perceived social support and both posttraumatic stress symptom severity (PTSS) and complex posttraumatic stress symptom severity (CPTSS); (b) associations between social support and PTSS/CPTSS; and (c) the potential moderating role of gender in the relationship between perceived social support and trauma-related distress.Method: A total of 2483 adults (Mage = 30yrs, 69.9% females) from 39 countries, who had been exposed to mixed trauma types, completed the Multidimensional Scale of Perceived Social Support and the International Trauma Questionnaire (which captures PTSS/CPTSS). Regression analyses examined associations between gender, perceived social support, and PTSS/CPTSS; and tested for gender by social support interactions in predicting PTSS/CPTSS scores. Models were adjusted for age and socioeconomic status.Results: In our cross-country sample, females had greater PTSS/CPTSS than males (B = .23 [95% CI 0.16, 0.30], p < .001; B = .20 [0.12, 0.27], p < .001; respectively), but there was no evidence of gender differences in perceived social support (B = .05 [-0.05, 0.16], p = .33). For both genders, low perceived social support was associated with higher PTSS/CPTSS (females: B = -.16 [-0.20, -0.12], p < .001; B = -.27 [-0.30, -0.24], p < .001; respectively; males: B = -.22 [-0.29, -0.15], p < .001; B = -.31 [-0.36, -0.26], p < .001; respectively), and for PTSS only we found weak evidence that this association was stronger for males vs. females (B = .07 [0.04, 0.14, p = .04).Conclusion: Individuals who feel more socially supported have lower trauma-related distress, and this association is similar in males and females. PTSD/CPTSD interventions may benefit from augmenting perceived social support, regardless of gender.; In our multi-country sample, females show higher levels of (complex) posttraumatic stress symptom severity than males.There is no evidence of gender differences in perceived social support.Greater perceived social support is associated with lower (complex) posttraumatic stress symptom severity across both genders.

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  • 24.
    Faria, V
    et al.
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Rosman, J B
    Henningson, S
    Marschner, A
    Åhs, F
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Linnman, C
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Pissiota, A
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Appel, L
    Eriksson, E
    Fredriksson, M
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Furmark, T
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Serotonin-1A receptor allelic variation and brain endophenotypes: A PET study of social phobia2006Conference paper (Refereed)
  • 25.
    Faria, Vanda
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Appel, Lieuwe
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology and Neuroscience, Duke University, Durham, NC, United States.
    Linnman, Clas
    P.A.I.N. Group, Department of Anesthesia, Childrens Hospital, Boston, MA, United States.
    Pissiota, Anna
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frans, Örjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Bani, Massimo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Pich, Emilio M
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy; F. Hoffman la Roche, Pharmaceutical Division, PRED, Basel, Switzerland.
    Jacobsson, Eva
    Uppsala University Hospital, Quintiles AB Phase I Services, Uppsala, Sweden.
    Wahlstedt, Kurt
    Uppsala University Hospital, Quintiles AB Phase I Services, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    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. 2222-32Article 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 correlated 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.

  • 26.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Clas
    Pissiota, Anna
    Frans, Örjan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bani, Massimo
    Bettica, Paolo
    Pich, Emilio Merlo
    Jacobsson, Eva
    Wahlstedt, Kurt
    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.
    Differences in Amygdala Responsivity Between Responders and Nonresponders to SSRIs in Patients with Social Anxiety Disorder2011In: Biol. Psychiatry 69, 70S-71S, 2011, Vol. 69Conference paper (Other academic)
    Abstract [en]

    Background: Selective serotonin reuptake inhibitors (SSRIs) are commonly accepted as the first line pharmacological therapy for anxiety disorders and depression. However, there is a high percentage of patients that fail to achieve satisfactory response with SSRI treatments. The neural mechanisms underlying effective and ineffective outcome with SSRIs are not well characterized. The amygdala has dense serotonergic innervation, and studies have suggested the amygdala to be a crucial brain target for SSRI treatment. This study aimed at investigating differences in amygdala responsivity between responders and nonresponders to SSRI treatments in patients with social anxiety disorder (SAD).

    Methods: Stress-related regional cerebral blood flow (rCBF) was measured in SAD patients (n=35) with 15O-water positron emission tomography (PET) during public speaking before and after 6-8 weeks of treatment with citalopram or paroxetine. Response rate was determined by the Clinical Global Impression-Improvement scale.

    Results: Within-group comparisons revealed reduced rCBF response bilaterally in the amygdala in responders (n=20) as well as in nonresponders (n=15). Between-group contrasts revealed a greater amygdala attenuation in responders (>nonresponders) in the left basolateral/basomedial (x-16, y-6, z-14, Z=1.66, Puncorr=0.024) and right ventrolateral subregions (x26, y-4, z-26, Z=2.12, Puncorr=0.009). However, greater rCBF attenuation in nonresponders (> responders) was observed in the left lateral amygdala (x-28, y-6, z-14, Z=2.38, Puncorr=0.005).

    Conclusions: Lowered amygdala responsivity does not seem to be exclusively related to clinical improvement in anxiety patients. In accordance with animal literature, our data suggest that amygdala subregions are functionally heterogeneous with regards to anxiolysis.

  • 27.
    Faria, Vanda
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Ågren, Thomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bah Rosman, J
    Henningsson, S
    Appel, L
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Linnman, Claes
    Oreland,
    Bani, M
    Pich, E M
    Eriksson, E
    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.
    Influence of the COMT Val158Met polymorphism on amygdala reactivity in social anxiety disorder.2009In: Biol. Psychiatry 65, 126S-126S, 2009, p. 420-Conference paper (Refereed)
  • 28.
    Faria, Vanda
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology and Neuroscience, Duke University, Durham, NC, USA.
    Appel, Lieuwe
    PET Centre, Uppsala University Hospital and Section of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Linnman, Clas
    P.A.I.N. Group, Department of Anesthesia, Children's Hospital, Boston, MA, USA.
    Bani, Massimo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    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. 1149-57Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: In patients with social anxiety disorder (SAD) it has been reported that selective serotonin reuptake inhibitors (SSRIs) and placebo induce anxiolytic effects by attenuating neural activity in overlapping amygdala subregions, i.e. left basolateral and right ventrolateral amygdala. However, it is not known whether these treatments inhibit amygdala subregions via similar or distinct brain pathways. As anxiolytic treatments may alter amygdala-frontal couplings we investigated differences and similarities in amygdala-frontal functional co-activation patterns between responders and nonresponders to SSRIs and placebo in patients with SAD. Positron emission tomography (PET) with oxygen-15-labeled water was used to measure anxiety-related regional cerebral blood flow in 72 patients with SAD before and after 6-8 wk of treatment under double-blind conditions. Functional couplings were evaluated with a seed region approach using voxel values from the left basolateral and right ventrolateral amygdala. Responders and nonresponders to SSRIs and placebo showed different treatment-induced co-activations between the left amygdala and the dorsolateral prefrontal cortex (dlPFC) as well as the rostral anterior cingulate cortex (ACC). Conjunction analysis suggested shared anxiolysis-dependent inverse co-activations in SSRI and placebo responders between the left amygdala-dlPFC and left amygdala-rostral ACC, and a shared positive co-activation between left amygdala-dorsal ACC. We demonstrate that amygdala-frontal co-activation patterns differentiate effective from ineffective anxiolytic treatments and that SSRI and placebo responders share overlapping neuromodulatory paths that may underlie improved emotion regulation and reduced expression of anxiety.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00343707.

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  • 29.
    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.
    Linnman, Clas
    Pissiota, Anna
    Palmqvist Michelgård, Åsa
    Zancan, S
    Bani, M
    Pich, E
    Appel, L
    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.
    Pretreatment Anterior Cingulate Activity Predicts Amygdala Attenuation in Social Phobic Placebo Responders2010In: Biol. Psychiatry 67, 34S-34S, 2010, p. 34S-34S 109Conference paper (Refereed)
  • 30.
    Frans, Örjan
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Åhs, Jill
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden.
    Bihre, Eva
    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.
    Distance to Threat and Risk of Acute and Posttraumatic Stress Disorder Following Bank Robbery: A longitudinal study2018In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 267, p. 461-466Article in journal (Refereed)
    Abstract [en]
    • Environmental factors surrounding trauma influencing PTSD risk are understudied.
    • Proximal distances to threatening individuals could increase PTSD risk directly or indirectly by increasing ASD risk.
    • Proximity to robber, ASD and PTSD was assessed in bank employees following robbery.
    • We found that proximity to robber increase PTSD risk indirectly by increasing ASD risk.
    • We speculate that proximity to threat may increase stress and arousal making trauma memories intrusive.
  • 31.
    Frans, Örjan
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Jill
    Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
    Bihre, Eva
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Distance to threat and risk of acute and posttraumatic stress disorder following bank robbery: A longitudinal study2018In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 267, p. 461-466, article id S0165-1781(17)31836-XArticle in journal (Refereed)
    Abstract [en]

    Identifying pathways through which environmental risk factors influence PTSD is important for understanding PTSD etiology. Here, we hypothesized that the physical proximity to threat influences PTSD risk by increasing ASD following trauma. One hundred six bank employees who had experienced a bank robbery participated in the study. A longitudinal design assessing ASD at day 2 and PTSD at day 30 was used to test the hypothesis. Participants also indicated their location in the bank at the time of the robbery. ASD was identified in 40 (38%) and PTSD in 16 (15%) of the robbery victims. Distance to the robber had a strong effect on ASD (OR 3.51, 95% CI 1.94-6.34) and a somewhat lesser effect on PTSD (OR 2.15, 95% CI 1.04-4.46), indicating that the effect of proximity to threat on PTSD 1 month following trauma could be mediated by its effect on ASD 2 days following trauma. Using structural equation modeling, we confirmed that the effect of distance on PTSD was fully mediated by ASD. These findings suggest that proximity to threat may increase PTSD risk by enhancing the acute stress response following trauma.

  • 32.
    Frick, A
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinica Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Linnman, C
    Department of Anesthesiology, Center for Pain and the Brain, Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
    Jonasson, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Appel, L
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Lubberink, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Långström, B
    Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Fredrikson, M
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, T
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [11C]GR2051712015In: Translational Psychiatry, 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 [11C]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.

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  • 33.
    Frick, A
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Palmquist, Å M
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Pissiota, A
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Wallenquist, U
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Fernandez, M
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Jonasson, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Appel, L
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Frans, Ö
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Lubberink, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Furmark, T
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    von Knorring, L
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fredrikson, M
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Alterations in the serotonergic and substance P systems in posttraumatic stress disorder2016In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 10, article id 1323Article in journal (Refereed)
  • 34.
    Frick, A
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Palmquist, Å M
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Pissiota, A
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Wallenquist, U
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Fernandez, M
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Jonasson, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Appel, L
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Frans, Ö
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Lubberink, M
    Department of Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
    Furmark, T
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    von Knorring, L
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Fredrikson, M
    Department of Psychology, Uppsala University, Uppsala, Sweden; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    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. 1400-7Article 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.

  • 35. Frick, Andreas
    et al.
    Björkstrand, Johannes
    Lubberink, Mark
    Eriksson, Allison
    Fredrikson, Mats
    Åhs, Fredrik
    Mid Sweden University, Faculty of Human Sciences, Department of Psychology and Social Work.
    Dopamine and fear memory formation in the human amygdala2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 3, p. 1704-1711Article in journal (Refereed)
    Abstract [en]

    Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

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  • 36.
    Frick, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Björkstrand, Johannes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Lund Univ, Dept Psychol, Lund, Sweden..
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Allison
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Åhs, Fredrik
    Mid Sweden Univ, Dept Psychol & Social Work, Östersund, Sweden..
    Dopamine and fear memory formation in the human amygdala2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 3, p. 1704-1711Article in journal (Refereed)
    Abstract [en]

    Learning which environmental cues that predict danger is crucial for survival and accomplished through Pavlovian fear conditioning. In humans and rodents alike, fear conditioning is amygdala-dependent and rests on similar neurocircuitry. Rodent studies have implicated a causative role for dopamine in the amygdala during fear memory formation, but the role of dopamine in aversive learning in humans is unclear. Here, we show dopamine release in the amygdala and striatum during fear learning in humans. Using simultaneous positron emission tomography and functional magnetic resonance imaging, we demonstrate that the amount of dopamine release is linked to strength of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala. Thus, like in rodents, formation of amygdala-dependent fear memories in humans seems to be facilitated by endogenous dopamine release, supporting an evolutionary conserved neurochemical mechanism for aversive memory formation.

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    fulltext
  • 37.
    Frick, Andreas
    et al.
    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.
    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.
    Jonasson, M
    Lubberink, M
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Increased serotonin synthesis and transporter availability in social anxiety disorder revealed by [11C]5-HTP and [11C]DASB PET imaging2014Conference paper (Refereed)
  • 38.
    Frick, Andreas
    et al.
    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.
    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.
    Jonasson, M
    Lubberink, M
    Åhs, Fredrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Increased serotonin transporter availability in social anxiety disorder revealed by [11C]DASB positron emission tomography2014Conference paper (Refereed)
  • 39.
    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.
    Appel, Lieuwe
    Jonasson, My
    Linnman, Clas
    Faria, Vanda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Wahlstedt, Kurt
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Pich, Emilio Merlo
    Bani, Massimo
    Bettica, Paolo
    Lubberink, Mark
    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.
    Reduced Serotonin Synthesis after Pharmacological Treatment of Social Anxiety Disorder2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 9, p. 90S-90S, article id 236Article in journal (Other academic)
  • 40.
    Frick, Andreas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Appel, Lieuwe
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Jonasson, My
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Wahlstedt, Kurt
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Bani, Massimo
    GlaxoSmithKline, Verona, Italy.
    Merlo Pich, Emilio
    GlaxoSmithKline, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Verona, Italy.
    Långström, Bengt
    Department of Chemistry, Uppsala University, Uppsala, Sweden.
    Lubberink, Mark
    Section of Nuclear Medicine and PET, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    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. 1775-1783, article id S0924-977X(16)30182-1Article in journal (Refereed)
    Abstract [en]

    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; 40mg), the NK1R antagonist GR205171 (n=6; 5mg; 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.

  • 41.
    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.

  • 42.
    Frick, Andreas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Engman, Jonas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Jonasson, My
    Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
    Alaie, Iman
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Björkstrand, Johannes
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frans, Örjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Faria, Vanda
    Department of Psychology, Uppsala University, Uppsala, Sweden. Center for Pain and the Brain, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.
    Linnman, Clas
    Department of Psychology, Uppsala University, Uppsala, Sweden. Center for Pain and the Brain, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts.
    Appel, Lieuwe
    Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
    Wahlstedt, Kurt
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Lubberink, Mark
    Department of Nuclear Medicine and Positron Emission Tomography, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.2015In: JAMA psychiatry, ISSN 2168-6238, 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.

  • 43. 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.

  • 44.
    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, 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.

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  • 45.
    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.

  • 46.
    Furmark, T
    et al.
    Uppsala University.
    Ahs, F
    Uppsala University.
    Linnman, C
    Pissiota, A
    Appel, L
    Rösman, J B
    Henningson, S
    L, Oreland
    Eriksson, E
    Fredriksson, M
    Uppsala University.
    Enhanced amygdalar activation during perception of negative affect in patients with social phobia carrying the short allele of the human serotonin transporter gene2006Conference paper (Refereed)
  • 47.
    Furmark, T
    et al.
    Uppsala University.
    Åhs, F
    Uppsala University.
    Linnman, C
    Uppsala University.
    Pissiota, A
    Michelgård, Å
    Uppsala University.
    Hellquist, A
    Hernefalk, S
    Flykt, K
    Appel, L
    Bani, M
    Merlo Pich, E
    Zancan, S
    Fredriksson, M
    Uppsala University.
    Amygdalar activity during emotional perception and experience in subjects with social phobia2005Conference paper (Other scientific)
  • 48.
    Furmark, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Appel, L
    Winqvist, I
    Michelgård, Åsa
    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.
    Bani, M
    Pich, E M
    Långström, B
    Fredrikson, Mats
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Elevated uptake of [C-11] 5-hydroxy-tryptophan in the amygdala in patients with social anxiety disorder: a PET study2009In: Biol. Psychiatry 65, 126S-127S, 2009, p. 421-Conference paper (Other academic)
    Abstract [en]

    Background: Social anxiety disorder (SAD) is associated with amygdala hyperresponsivity and imbalances in serotonergic neurotransmission. We have previously noted altered uptake of carbon-11 labelled 5-hydroxytryptophan (5-HTP) in a small sample of patients with SAD, suggesting deficiencies in presynaptic serotonin synthesis. In the present study, positron emission tomography (PET) was used to assess uptake of [11C]5-HTP in a larger sample of patients with SAD compared with age and sex-matched healthy controls. Methods: PET-data were available for 17 patients (8 females, age 33±8 years) diagnosed with SAD and for 17 healthy controls (9 females, age 35±10 years). Accumulation of the [11C]5-HTP tracer was assessed at Uppsala Imanet during 60 minutes in the resting state. Parametric images were generated using the graphical reference Patlak method assuming irreversible trapping of [11C]5-HTP from 11-60 minutes. Cerebellum was selected as reference region after correction for the decarboxylation rate of [11C]5-HTP. Exploratory and amygdala focused analyses were performed using statistical parametric mapping (SPM2). Results: Patients with SAD had significantly higher [11C]5-HTP uptake than controls in several regions including the superior, medial and inferior frontal gyrus, anterior cingulate cortex, hippocampus and lentiform nucleus, all in the left hemisphere. Region of interest analyses also revealed significantly higher uptake (SAD > controls) in the left (x-28 y-4 z-12; T=3.16) and right (x24 y1 z-15; T=2.82) amygdala (p<0.05 corrected). Conclusions: Higher [11C]5-HTP uptake, suggesting an elevated serotonin synthesis rate, was noted in patients with SAD compared to healthy controls predominantly in frontal and temporal regions including the amygdala.

  • 49.
    Furmark, Tomas
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Appel, Lieuwe
    Uppsala Imanet, GE Healthcare, Uppsala, Sweden.
    Henningsson, Susanne
    Department ofPharmacology, Göteborg University, Göteborg, Sweden.
    Åhs, Fredrik
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Faria, Vanda
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Linnman, Clas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Pissiota, Anna
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frans, Orjan
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Bani, Massimo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Bettica, Paolo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Pich, Emilio Merlo
    GlaxoSmithKline, Medicine Research Centre, Verona, Italy.
    Jacobsson, Eva
    Quintiles AB Phase IServices, Uppsala, Sweden.
    Wahlstedt, Kurt
    Quintiles AB Phase IServices, Uppsala, Sweden.
    Oreland, Lars
    Department of Neuroscience, Pharmacology, Uppsala University, Uppsala, Sweden.
    Långström, Bengt
    Uppsala Imanet, GE Healthcare, Uppsala, Sweden; Department ofBiochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden.
    Eriksson, Elias
    Department ofPharmacology, Göteborg University, Göteborg, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    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.

  • 50.
    Furmark, Tomas
    et al.
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Appel, Lieuwe
    Michelgård, Asa
    Wahlstedt, Kurt
    Åhs, Fredrik
    Uppsala University, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Faculty of Social Sciences, Department of Psychology.
    Zancan, Stefano
    Jacobsson, Eva
    Flyckt, Karin
    Grohp, Magnus
    Bergstrom, Mats
    Pich, Emilio Merlo
    Nilsson, Lars-Göran
    Bani, Massimo
    Långström, Bengt
    Fredrikson, Mats
    Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171, citalopram, or placebo.2005In: Biol Psychiatry, ISSN 0006-3223, Vol. 58, no 2, p. 132-42Article in journal (Other scientific)
    Abstract [en]

    BACKGROUND: Evidence is accumulating that pharmacological blockade of the substance P preferring neurokinin-1 (NK1) receptor reduces anxiety. This study compared the effects of an NK1 receptor antagonist, citalopram, and placebo on brain activity and anxiety symptoms in social phobia. METHODS: Thirty-six patients diagnosed with social phobia were treated for 6 weeks with the NK1 antagonist GR205171 (5 mg), citalopram (40 mg), or matching placebo under randomized double-blind conditions. GR205171 was administered for 4 weeks preceded by 2 weeks of placebo. Before and after treatment, regional cerebral blood flow (rCBF) during a stressful public speaking task was assessed using oxygen-15 positron emission tomography. Response rate was determined by the Clinical Global Impression Improvement Scale. RESULTS: Patients improved to a larger extent with the NK1 antagonist (41.7% responders) and citalopram (50% responders), compared with placebo (8.3% responders). Within- and between-group comparisons showed that symptom improvement was paralleled by a significantly reduced rCBF response to public speaking in the rhinal cortex, amygdala, and parahippocampal-hippocampal regions. The rCBF pattern was corroborated in follow-up analyses of responders and subjects showing large state anxiety reduction. CONCLUSIONS: Short-term administration of GR205171 and citalopram alleviated social anxiety. Neurokinin-1 antagonists may act like serotonin reuptake inhibitors by attenuating neural activity in a medial temporal lobe network.

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