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  • 1.
    Austin, Christine
    et al.
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, One Gustave L Levy Pl, New York, NY USA.
    Curtin, Paul
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, One Gustave L Levy Pl, New York, NY USA.
    Curtin, Austen
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, One Gustave L Levy Pl, New York, NY USA.
    Gennings, Chris
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, One Gustave L Levy Pl, New York, NY USA.
    Arora, Manish
    Icahn Sch Med Mt Sinai, Dept Environm Med & Publ Hlth, One Gustave L Levy Pl, New York, NY USA.
    Tammimies, Kristiina
    Karolinska Inst, Karolinska Inst Ctr Neurodev Disorders KIND, Ctr Psychiat Res, Dept Womens & Childrens Hlth, Stockholm, Sweden; Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden.
    Isaksson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Karolinska Inst, Karolinska Inst Ctr Neurodev Disorders KIND, Ctr Psychiat Res, Dept Womens & Childrens Hlth, Stockholm, Sweden; Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden.
    Willfors, Charlotte
    Karolinska Inst, Karolinska Inst Ctr Neurodev Disorders KIND, Ctr Psychiat Res, Dept Womens & Childrens Hlth, Stockholm, Sweden; Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden; Karolinska Inst, Dept Mol Med & Surg, Ctr Mol Med, Stockholm, Sweden.
    Bölte, Sven
    Karolinska Inst, Karolinska Inst Ctr Neurodev Disorders KIND, Ctr Psychiat Res, Dept Womens & Childrens Hlth, Stockholm, Sweden; Stockholm Cty Council, Stockholm Hlth Care Serv, Stockholm, Sweden; Curtin Univ, Sch Occupat Therapy Social Work & Speech Pathol, Curtin Autism Res Grp, Essential Partner Autism CRC, Perth, WA, Australia.
    Dynamical properties of elemental metabolism distinguish attention deficit hyperactivity disorder from autism spectrum disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 238Article in journal (Refereed)
    Abstract [en]

    Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions of overlapping etiologies and phenotypes. For ASD, we recently reported altered elemental metabolic patterns in the form of short and irregular zinc and copper cycles. Here, we extend the application of these biomarkers of prenatal and early postnatal elemental metabolism to distinguish between individuals diagnosed with ADHD and/or ASD and neurotypical controls. We recruited twins discordant for ADHD, ASD and other neurodevelopmental diagnoses from national twin studies in Sweden (N = 74) diagnosed according to DSM-5 clinical consensus and standardized psychiatric instruments. Detailed temporal profiles of exposure to 10 metals over the prenatal and early childhood periods were measured using tooth biomarkers. We used recurrence quantification analysis (RQA) to characterize properties of cyclical metabolic patterns of these metals. Regularity (determinism) and complexity (entropy) of elemental cycles was consistently reduced in ADHD for cobalt, lead, and vanadium (determinism: cobalt, β = -0.03, P = 0.017; lead, β = -0.03, P = 0.016; and vanadium, β = -0.03, P = 0.01. Entropy: cobalt, β = -0.13, P = 0.017; lead, β = -0.18, P = 0.016; and vanadium, β = -0.15, P = 0.008). Further, we found elemental pathways and dynamical features specific to ADHD vs ASD, and unique characteristics associated with ADHD/ASD combined presentation. Dysregulation of cyclical processes in elemental metabolism during prenatal and early postnatal development not only encompasses pathways shared by ADHD and ASD, but also comprise features specific to either condition.

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  • 2.
    Bazov, Igor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karpyak, Victor M.
    Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN 55905 USA.
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, article id 122Article in journal (Refereed)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

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  • 3.
    Bazov, Igor
    et al.
    Uppsala University, Uppsala, Sweden.
    Sarkisyan, Daniil
    Uppsala University, Uppsala, Sweden.
    Kononenko, Olga
    Uppsala University, Uppsala, Sweden.
    Watanabe, Hiroyuki
    Uppsala University, Uppsala, Sweden.
    Karpyak, Victor M
    Mayo Clinic College of Medicine, Rochester, USA.
    Yakovleva, Tatiana
    Uppsala University, Uppsala, Sweden.
    Bakalkin, Georgy
    Uppsala University, Uppsala, Sweden.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, no 1, article id 122Article in journal (Refereed)
    Abstract [en]

    Molecular changes in cortical areas of addicted brain may underlie cognitive impairment and loss of control over intake of addictive substances and alcohol. Prodynorphin (PDYN) gives rise to dynorphin (DYNs) opioid peptides which target kappa-opioid receptor (KOR). DYNs mediate alcohol-induced impairment of learning and memory, while KOR antagonists block excessive, compulsive-like drug and alcohol self-administration in animal models. In human brain, the DYN/KOR system may undergo adaptive changes, which along with neuronal loss, may contribute to alcohol-associated cognitive deficit. We addressed this hypothesis by comparing the expression levels and co-expression (transcriptionally coordinated) patterns of PDYN and KOR (OPRK1) genes in dorsolateral prefrontal cortex (dlPFC) between human alcoholics and controls. Postmortem brain specimens of 53 alcoholics and 55 controls were analyzed. PDYN was found to be downregulated in dlPFC of alcoholics, while OPRK1 transcription was not altered. PDYN downregulation was confined to subgroup of subjects carrying C, a high-risk allele of PDYN promoter SNP rs1997794 associated with alcoholism. Changes in PDYN expression did not depend on the decline in neuronal proportion in alcoholics, and thereby may be attributed to transcriptional adaptations in alcoholic brain. Absolute expression levels of PDYN were lower compared to those of OPRK1, suggesting that PDYN expression is a limiting factor in the DYN/KOR signaling, and that the PDYN downregulation diminishes efficacy of DYN/KOR signaling in dlPFC of human alcoholics. The overall outcome of the DYN/KOR downregulation may be disinhibition of neurotransmission, which when overactivated could contribute to formation of alcohol-related behavior.

  • 4.
    Bejerot, Susanne
    et al.
    Örebro University, School of Medical Sciences. Department of Psychiatry, School of Medical Sciences, Örebro University, Örebro, Sweden; University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hesselmark, Eva
    Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Solna, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    The Cunningham Panel is an unreliable biological measure2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 49Article in journal (Refereed)
  • 5.
    Bejerot, Susanne
    et al.
    Örebro University, School of Medical Sciences. University Health Care Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Solna, Sweden.
    Klang, Albin
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Hesselmark, Eva
    Center for Psychiatry Research, Department of clinical neuroscience, Karolinska Institutet, Solna, Sweden; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
    The Cunningham Panel: concerns remain2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 224Article in journal (Refereed)
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    The Cunningham Panel: concerns remain
  • 6.
    Bendre, M.
    et al.
    Uppsala Univ, Dept Neurosci, S-75124 Uppsala, Sweden..
    Comasco, E.
    Uppsala Univ, Dept Neurosci, S-75124 Uppsala, Sweden..
    Nylander, I.
    Uppsala Univ, Dept Pharmaceut Biosci, SE-75124 Uppsala, Sweden..
    Nilsson, Kent W.
    Uppsala Univ, Cty Hosp, Ctr Clin Res, Vasteras, Sweden..
    Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e690Article in journal (Refereed)
    Abstract [en]

    Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress-and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.

  • 7.
    Bendre, Megha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Kent W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation.: Maoa,ELS and alcohol2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e690Article in journal (Refereed)
    Abstract [en]

    Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.

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  • 8.
    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.

  • 9. 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.

  • 10.
    Bernabe, Beatriz Penalver
    et al.
    Univ Illinois, Coll Engn & Med, Dept Biomed Engn, Chicago, IL 60607 USA.;Univ Illinois, Ctr Bioinformat & Quantitat Biol, Chicago, IL 60607 USA..
    Maki, Pauline M.
    Univ Illinois, Coll Med, Dept Psychol, Chicago, IL USA.;Univ Illinois, Coll Med, Dept Psychiat, Chicago, IL USA.;Univ Illinois, Coll Med, Dept Obstet & Gynecol, Chicago, IL 60612 USA..
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Eisenlohr-Moul, Tory
    Univ Illinois, Coll Med, Dept Psychol, Chicago, IL USA.;Univ Illinois, Coll Med, Dept Psychiat, Chicago, IL USA..
    Tussing-Humphreys, Lisa
    Univ Illinois, Coll Appl Hlth Sci, Dept Kinesiol & Nutr, Chicago, IL USA..
    Carroll, Ian M.
    Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27515 USA..
    Meltzer-Brody, Samantha
    Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA..
    Gilbert, Jack A.
    Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.;Univ Calif San Diego, Scripps Inst Oceanog, La Jolla, CA 92093 USA..
    Kimmel, Mary C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Reproductive Health Research. Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA..
    Interactions between perceived stress and microbial-host immune components: two demographically and geographically distinct pregnancy cohorts2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, article id 3Article in journal (Refereed)
    Abstract [en]

    Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study.

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  • 11.
    Bernardi, R. E.
    et al.
    Heidelberg University, Germany.
    Zohsel, K.
    Heidelberg University, Germany.
    Hirth, N.
    Heidelberg University, Germany.
    Treutlein, J.
    Heidelberg University, Germany.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Laucht, M.
    Heidelberg University, Germany.
    Spanagel, R.
    Heidelberg University, Germany.
    Sommer, W. H.
    Heidelberg University, Germany.
    A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no e861Article in journal (Refereed)
    Abstract [en]

    It has been proposed that vulnerability to nicotine addiction is moderated by variation at the mu-opioid receptor locus (OPRM1), but results from human studies vary and prospective studies based on genotype are lacking. We have developed a humanized mouse model of the most common functional OPRM1 polymorphism rs1799971_A4G (A118G). Here we use this model system together with a cohort of German youth to examine the role of the OPRM1 A118G variation on nicotine reward. Nicotine reinforcement was examined in the humanized mouse model using i.v. self-administration. Male (n = 17) and female (n = 26) mice homozygous either for the major human A allele (AA) or the minor G allele (GG) underwent eight daily 2 h sessions of nicotine self-administration. Furthermore, male (n = 104) and female (n = 118) subjects homozygous for the A allele or carrying the G allele from the Mannheim Study of Children at Risk were evaluated for pleasurable and unpleasant experiences during their initial smoking experience. A significant sex-by-genotype effect was observed for nicotine self-administration. Male 118GG mice demonstrated higher nicotine intake than male 118AA mice, suggesting increased nicotine reinforcement. In contrast, there was no genotype effect in female mice. Human male G allele carriers reported increased pleasurable effects from their first smoking experience, as compared to male homozygous A, female G and female homozygous A allele carriers. The 118G allele appears to confer greater sensitivity to nicotine reinforcement in males, but not females.

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  • 12.
    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.

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  • 13.
    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.

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  • 14.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, no 3, article id e1050Article in journal (Refereed)
    Abstract [en]

    The enzyme phosphodiesterase 10A (PDE10A) is abundant in striatal medium spiny neurons and has been implicated in the pathophysiology of schizophrenia in animal models and is investigated as a possible new pharmacological treatment target. A reduction of prefrontal cortical thickness is common in schizophrenia, but how this relates to PDE10A expression is unknown. Our study aim was to compare, we believe for the first time, the striatal non-displaceable binding potential (BPND) of the new validated PDE10A ligand [(11)C]Lu AE92686 between patients with schizophrenia and healthy controls. Furthermore, we aimed to assess the correlation of PDE10A BPND to cortical thickness. Sixteen healthy male controls and 10 male patients with schizophrenia treated with clozapine, olanzapine or quetiapine were investigated with positron emission tomography (PET) and magnetic resonance imaging (MRI). Striatal binding potential (BPND) of [(11)C]Lu AE92686 was acquired through dynamic PET scans and cortical thickness by structural MRI. Clinical assessments of symptoms and cognitive function were performed and the antipsychotic dosage was recorded. Patients with schizophrenia had a significantly lower BPND of [(11)C]Lu AE92686 in striatum (P=0.003) than healthy controls. The striatal BPND significantly correlated to cortical thickness in the medial prefrontal cortex and superior frontal gyrus across patients with schizophrenia and healthy controls. No significant correlation was observed between the BPND for [(11)C]Lu AE92686 in striatum and age, schizophrenia symptoms, antipsychotic dosage, coffee consumption, smoking, duration of illness or cognitive function in the patients. In conclusion, PDE10A may be important for functioning in the striato-cortical interaction and in the pathophysiology of schizophrenia.

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  • 15.
    Bostrom, Adrian Desai E.
    et al.
    Umea Univ, Dept Clin Sci, Psychiat, Umea, Sweden.;Karolinska Univ Hosp, Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm Hlth Care Serv, SE-17176 Stockholm, Sweden..
    Andersson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Karolinska Inst, Dept Clin Neurosci, Psychol, Stockholm, Sweden.;Uppsala Univ, Ctr Clin Res Dalarna, Falun, Sweden..
    Jamshidi, Esmail
    Umea Univ, Dept Clin Sci, Psychiat, Umea, Sweden..
    Wilczek, Alexander
    Karolinska Inst Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Nilsonne, Asa
    Karolinska Inst Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Rask-Andersen, Mathias
    Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Uppsala, Sweden..
    asberg, Marie
    Karolinska Inst Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Jokinen, Jussi
    Umea Univ, Dept Clin Sci, Psychiat, Umea, Sweden.;Karolinska Univ Hosp, Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm Hlth Care Serv, SE-17176 Stockholm, Sweden..
    Accelerated epigenetic aging in women with emotionally unstable personality disorder and a history of suicide attempts2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 66Article in journal (Refereed)
    Abstract [en]

    Emotional unstable personality disorder (EUPD; previously borderline personality disorder, BPD) is associated with excess natural-cause mortality, comorbid medical conditions, poor health habits and stress related epigenomic alterations. Previous studies demonstrated that GrimAge - a state-of-the-art epigenetic age (EA) estimator - strongly predicts mortality risk and physiological dysregulation. Herein, we utilize the GrimAge algorithm to investigate whether women with EUPD and a history of recent suicide attempts exhibit EA acceleration (EAA) in comparison to healthy controls. Genome-wide methylation patterns were measured using the Illumina Infinum Methylation Epic BeadChip in whole blood from 97 EUPD patients and 32 healthy controls. The control group was significantly older (p < 0.0001) and reported lesser exposure to violent behavior in both youth and adulthood (p < 0.0001). Groups were otherwise comparable regarding gender, BMI, or tobacco usage (p > 0.05). EA estimator DNAmGrimAge exceeded chronological age by 8.8 and 2.3 years in the EUPD and control group, respectively. Similarly, EAA marker AgeAccelGrim was substantially higher in EUPD subjects when compared to controls, in both univariate and multivariate analyzes (p < 0.00001). Tobacco usage conferred substantial within-group effects on the EA-chronological age difference, i.e., 10.74 years (SD = 4.19) compared to 6.00 years (SD = 3.10) in the non-user EUPD group (p < 0.00001). Notably, past alcohol and substance abuse, use of psychotropic medications, global assessment of functioning, self-reported exposure to violent behavior in youth and adulthood, later completed suicide (N = 8) and age at first suicide attempt did not predict EAA in the EUPD group (p > 0.05). These results underscore the importance of addressing medical health conditions along with low-cost preventative interventions aimed at improving somatic health outcomes in EUPD, such as efforts to support cessation of tobacco use. The independency of GrimAge to other EA algorithms in this group of severely impaired EUPD patients, suggest it may have unique characteristics to evaluate risk of adverse health outcomes in context of psychiatric disorders.

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  • 16.
    Boström, Adrian Desai E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, Stockholm, Sweden.
    Andersson, Peter
    Department of Clinical Neuroscience/Psychology, Karolinska Institute, Stockholm, Sweden; Centre for Clinical Research Dalarna, Uppsala University, Falun, Sweden.
    Jamshidi, Esmail
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Wilczek, Alexander
    Department of Clinical Sciences, Karolinska Institutet at Danderyd Hospital, Stockholm, Sweden.
    Nilsonne, Åsa
    Department of Clinical Sciences, Karolinska Institutet at Danderyd Hospital, Stockholm, Sweden.
    Rask-Andersen, Mathias
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Åsberg, Marie
    Department of Clinical Sciences, Karolinska Institutet at Danderyd Hospital, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, and Stockholm Health Care Services, Region Stockholm, Karolinska University Hospital, Stockholm, Sweden.
    Accelerated epigenetic aging in women with emotionally unstable personality disorder and a history of suicide attempts2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 66Article in journal (Refereed)
    Abstract [en]

    Emotional unstable personality disorder (EUPD; previously borderline personality disorder, BPD) is associated with excess natural-cause mortality, comorbid medical conditions, poor health habits and stress related epigenomic alterations. Previous studies demonstrated that GrimAge – a state-of-the-art epigenetic age (EA) estimator – strongly predicts mortality risk and physiological dysregulation. Herein, we utilize the GrimAge algorithm to investigate whether women with EUPD and a history of recent suicide attempts exhibit EA acceleration (EAA) in comparison to healthy controls. Genome-wide methylation patterns were measured using the Illumina Infinum Methylation Epic BeadChip in whole blood from 97 EUPD patients and 32 healthy controls. The control group was significantly older (p < 0.0001) and reported lesser exposure to violent behavior in both youth and adulthood (p < 0.0001). Groups were otherwise comparable regarding gender, BMI, or tobacco usage (p > 0.05). EA estimator DNAmGrimAge exceeded chronological age by 8.8 and 2.3 years in the EUPD and control group, respectively. Similarly, EAA marker AgeAccelGrim was substantially higher in EUPD subjects when compared to controls, in both univariate and multivariate analyzes (p < 0.00001). Tobacco usage conferred substantial within-group effects on the EA-chronological age difference, i.e., 10.74 years (SD = 4.19) compared to 6.00 years (SD = 3.10) in the non-user EUPD group (p < 0.00001). Notably, past alcohol and substance abuse, use of psychotropic medications, global assessment of functioning, self-reported exposure to violent behavior in youth and adulthood, later completed suicide (N = 8) and age at first suicide attempt did not predict EAA in the EUPD group (p > 0.05). These results underscore the importance of addressing medical health conditions along with low-cost preventative interventions aimed at improving somatic health outcomes in EUPD, such as efforts to support cessation of tobacco use. The independency of GrimAge to other EA algorithms in this group of severely impaired EUPD patients, suggest it may have unique characteristics to evaluate risk of adverse health outcomes in context of psychiatric disorders.

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  • 17.
    Brundin, L.
    et al.
    Van Andel Research Institute, MI 49503 USA.
    Sellgren, C. M.
    Karolinska Institute, Sweden; Broad Institute MIT and Harvard, MA USA; Massachusetts Gen Hospital, MA USA.
    Lim, C. K.
    Macquarie University, Australia.
    Grit, J.
    Van Andel Research Institute, MI 49503 USA.
    Palsson, E.
    Gothenburg University, Sweden.
    Landen, M.
    Gothenburg University, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Karolinska Institute, Sweden.
    Lundgren, Kristoffer
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Brundin, P.
    Van Andel Research Institute, MI 49503 USA.
    Fuchs, D.
    Medical University of Innsbruck, Austria.
    Postolache, T. T.
    University of Maryland, MD 21201 USA; Rocky Mt MIRECC, CO USA.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Guillemin, G. J.
    Macquarie University, Australia; NHMRC Centre Research Excellence Suicide Prevent CRESP, Australia.
    Erhardt, S.
    Karolinska Institute, Sweden.
    An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no e865Article in journal (Refereed)
    Abstract [en]

    Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-D-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (Pamp;lt;0.001) and blood (P=0.001 and Pamp;lt;0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

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  • 18.
    Carlsson, Torkel
    et al.
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Child and Adolescent Psychiatry, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; PRIMA Child and Adult Psychiatry, Stockholm, Sweden.
    Rosenqvist, Mina
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Butwicka, Agnieszka
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Child and Adolescent Psychiatry Stockholm, Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lundström, Sebastian
    Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden; Centre for Ethics, Law, and Mental Health, University of Gothenburg, Gothenburg, Sweden.
    Pan, Pei-Yin
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Lundin Remnélius, Karl
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Taylor, Mark J.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bölte, Sven
    Karolinska Institutet, Stockholm, Sweden; Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden; Curtin Autism Research Group, Curtin School of Allied Health, Curtin University, Perth, Western Australia.
    Association of cumulative early medical factors with autism and autistic symptoms in a population-based twin sample2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 73Article in journal (Refereed)
    Abstract [en]

    Although highly heritable, environment also contributes to the etiology of autism spectrum disorder (ASD), with several specific environmental factors previously suggested. A registry-linked population-based twin cohort of 15,701 pairs (586 individuals with an ASD diagnosis), was established within the Child and Adolescent Twin Study in Sweden. Participants were evaluated for autistic symptoms at age 9 using the Autism-Tics, ADHD and other Comorbidities parental interview. A series of binary cut-offs indicated whether participants scored over various ASD symptom percentiles. Three early medical factors previously associated with ASD, beyond familial confounding (low birth weight, congenital malformations and perinatal hypoxia), were summed up creating an individual cumulative exposure load. A series of unconditional logistic regressions between all individuals and conditional regressions within twin pairs were performed for each outcome and exposure level. Between all individuals increasing cumulative early exposure loads were associated with increasing risk of ASD diagnosis (OR 3.33 (95%CI 1.79-6.20) for three exposures) and autistic symptoms (ranging from OR 2.12 (1.57-2.86) for three exposures at the 55th symptom percentile cut-off to OR 3.39 (2.2-5.24) at the 95th). Within twin pairs, the association between three exposures and an ASD diagnosis remained similar, but not statistically significant (OR 2.39 (0.62-9.24)). Having a higher load of early cumulative exposure was consistently associated with autistic symptoms after adjusting for familial confounding and sex (OR 3.45 (1.66-7.15) to OR 7.36 (1.99-27.18)). This study gives support to the cumulative stress hypothesis of ASD, and the dimensional model regarding environmental exposures, after adjustment for familial confounding.

  • 19.
    Carolina Dalmasso, Maria
    et al.
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Ignacio Brusco, Luis
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina;UBA, CABA, Fac Med, Dept Ciencias Fisiol UAII, Buenos Aires, DF, Argentina;Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Olivar, Natividad
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina;UBA, CABA, Fac Med, Dept Ciencias Fisiol UAII, Buenos Aires, DF, Argentina.
    Muchnik, Carolina
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Hanses, Claudia
    Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany.
    Milz, Esther
    Univ Cologne, Dept Psychiat Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany.
    Becker, Julian
    Univ Bonn, Dept Psychiat & Psychotherapy, D-53127 Bonn, Germany.
    Heilmann-Heimbach, Stefanie
    Univ Bonn, Sch Med, Inst Human Genet, D-53127 Bonn, Germany;Univ Hosp, D-53127 Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany.
    Hoffmann, Per
    Univ Bonn, Sch Med, Inst Human Genet, D-53127 Bonn, Germany;Univ Hosp, D-53127 Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany;Univ Basel, Univ Hosp, Div Med Genet, CH-4058 Basel, Switzerland;Univ Basel, Dept Biomed, CH-4058 Basel, Switzerland.
    Prestia, Federico A.
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Galeano, Pablo
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Sanchez Avalos, Mariana Soledad
    Programa Adulto Mayor, Minist Salud Provi Jujuy, San Salvador De Jujuy, Jujuy, Argentina.
    Eduardo Martinez, Luis
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Estela Carulla, Mariana
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Javier Azurmendi, Pablo
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Liberczuk, Cynthia
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Fezza, Cristina
    UBA, CABA, Inst Invest Med Lanari, Lab Bioquim Mol,Fac Med, Buenos Aires, DF, Argentina.
    Sampano, Marcelo
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Fierens, Maria
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Jemar, Guillermo
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Solis, Patricia
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Medel, Nancy
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Lisso, Julieta
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Sevillano, Zulma
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Bosco, Paolo
    Inst Ricovero Cura Carattere Sci IRCCS, Assoc Oasi Maria Santissima Srl, Troina, Italy.
    Bossu, Paola
    Spalletta, Gianfranco
    IRCCS Santa Lucia Fdn, Neuropsychiat Lab, Dept Clin & Behav Neurol, Rome, Italy.
    Galimberti, Daniela
    Univ Milan, IRCCS Osped Maggiore Policlin, Fdn Ca Granda, Neurodegenerat Dis Ctr,Ctr Dino Ferrari, Milan, Italy.
    Mancuso, Michelangelo
    Univ Pisa, Neurol Inst, Dept Expt & Clin Med, Pisa, Italy.
    Nacmias, Benedetta
    Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Dept Neurosci, NEUROFARBA, Florence, Italy.
    Sorbi, Sandro
    Univ Florence, Dept Neurosci Psychol Drug Res & Child Hlth, Dept Neurosci, NEUROFARBA, Florence, Italy;IRCCS Don Carlo Gnocchi, Florence, Italy.
    Mecocci, Patrizia
    Univ Perugia, Dept Med, Sect Gerontol & Geriatr, Perugia, Italy.
    Pilotto, Alberto
    IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, San Giovanni Rotondo, Italy;IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Gerontol Geriatr Res Lab, San Giovanni Rotondo, Italy.
    Caffarra, Paolo
    Univ Parma, DIMEC, Sect Neurosci, Parma, Italy;FERB, Alzheimer Ctr, Bergamo, Italy.
    Panza, Francesco
    Univ Bari Aldo Moro, Dept Basic Med Neurosci & Sense Organs, Neurodegenerat Dis Unit, Bari, Italy.
    Bullido, Maria
    Hosp Paz IdiPAZ, Inst Invest Sanitaria, Madrid, Spain;Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain;UAM, CSIC, Ctr Biol Mol Severo Ochoa, Madrid, Spain.
    Clarimon, Jordi
    Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain;Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst, Memory Unit,Neurol Dept & Sant Pau, Barcelona, Spain.
    Sanchez-Juan, Pascual
    Univ Cantabria, Marques Valdecilla Univ Hosp, Neurol Serv, Santander, Spain;Univ Cantabria, CIBERNED, Marques Valdecilla Univ Hosp, Santander, Spain;IDIVAL, Santander, Spain.
    Coto, Eliecer
    Univ Cent Asturias, Mol Genet Lab Hosp, Oviedo, Spain.
    Sanchez-Garcia, Florentino
    Hosp Univ Gran Canaria Doctor Negrin, Immunol Serv, Las Palmas Gran Canaria, Spain.
    Graff, Caroline
    Karolinska Univ Hosp, Theme Aging, Genet Unit, Solna, Sweden;Karolinska Inst, Dept NVS, Div Neurogeriatr, Bioclin J10-20, Solna, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bellenguez, Celine
    INSERM, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, F-59000 Lille, France;Inst Pasteur, F-59000 Lille, France;Univ Lille, U1167, Excellence Lab LabEx DISTALZ, F-59000 Lille, France.
    Miguel Castano, Eduardo
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Kairiyama, Claudia
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Gustavo Politis, Daniel
    Hosp Interzonal Gen Agudos Eva Peron, Buenos Aires, DF, Argentina.
    Kochen, Silvia
    Univ Arturo Jauretche, Hosp El Cruce Dr Nestor Kirchner, CONICET, Neurosci & Complex Syst Unit EnyS, Buenos Aires, DF, Argentina.
    Scaro, Horacio
    Programa Adulto Mayor, Minist Salud Provi Jujuy, San Salvador De Jujuy, Jujuy, Argentina.
    Maier, Wolfgang
    German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany;Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany.
    Jessen, Frank
    German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany;Univ Cologne, Dept Psychiat & Psychotherapy, D-50937 Cologne, Germany.
    Alberto Mangone, Carlos
    UBA, Fac Med, Ctr Neuropsiquiatria Neurol Conducta CENFCON, CABA, Buenos Aires, DF, Argentina.
    Lambert, Jean-Charles
    INSERM, U1167, RID AGE Risk Factors & Mol Determinants Aging Rel, F-59000 Lille, France;Inst Pasteur, F-59000 Lille, France;Univ Lille, U1167, Excellence Lab LabEx DISTALZ, F-59000 Lille, France.
    Morelli, Laura
    Consejo Nacl Invest Cient & Tecn, IIBBA, Fdn Inst Leloir, Lab Amyloidosis & Neurodegenerat,CABA, Buenos Aires, DF, Argentina.
    Ramirez, Alfredo
    Univ Cologne, Dept Psychiat Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany;Univ Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany.
    Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 55Article in journal (Refereed)
    Abstract [en]

    Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

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    FULLTEXT01
  • 20.
    Carvalho, Andre F.
    et al.
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Solmi, Marco
    Univ Padua, Italy; Kings Coll London, England.
    Sanches, Marcos
    Ctr Addict and Mental Hlth CAMH, Canada; Krembil Ctr NeuroInformat, Canada.
    Machado, Myrela O.
    Womens Coll Hosp, Canada.
    Stubbs, Brendon
    South London and Maudsley NHS Fdn Trust, England; Kings Coll London, England.
    Ajnakina, Olesya
    Kings Coll London, England.
    Sherman, Chelsea
    Sunnybrook Res Inst, Canada.
    Sun, Yue Ran
    Sunnybrook Res Inst, Canada.
    Liu, Celina S.
    Sunnybrook Res Inst, Canada.
    Brunoni, Andre R.
    Univ Sao Paulo, Brazil.
    Pigato, Giorgio
    Univ Padua, Italy.
    Fernandes, Brisa S.
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Bortolato, Beatrice
    Dept Mental Hlth ULSS 8 Berica, Italy.
    Husain, Muhammad I
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Firth, Joseph
    Western Sydney Univ, Australia; Univ Manchester, England.
    Cosco, Theodore D.
    Simon Fraser Univ, Canada; Univ Oxford, England.
    Maes, Michael
    Chulalongkorn Univ, Thailand; Deakin Univ, Australia.
    Berk, Michael
    Deakin Univ, Australia; Orygen, Australia; Univ Melbourne, Australia; Univ Melbourne, Australia.
    Lanctot, Krista L.
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada; Sunnybrook Res Inst, Canada; Sunnybrook Res Inst, Canada; Univ Toronto, Canada.
    Vieta, Eduard
    Univ Barcelona, Spain.
    Pizzagalli, Diego A.
    Harvard Med Sch, MA 02478 USA.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Fusar-Poli, Paolo
    Kings Coll London, England; South London and Maudsley Natl Hlth Serv Fdn Trust, England; Univ Pavia, Italy.
    Kurdyak, Paul A.
    Univ Toronto, Canada; Canada Inst Clin Evaluat Sci ICES, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Fornaro, Michele
    Univ Sch Med Federico II, Italy.
    Rehm, Jurgen
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada; CAMH, Canada; Univ Toronto, Canada; Tech Univ Dresden, Germany; Tech Univ Dresden, Germany; Univ Toronto, Canada; IM Sechenov First Moscow State Med Univ, Russia.
    Herrmann, Nathan
    Univ Toronto, Canada; Sunnybrook Res Inst, Canada; Sunnybrook Res Inst, Canada.
    Evidence-based umbrella review of 162 peripheral biomarkers for major mental disorders2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1Article, review/survey (Refereed)
    Abstract [en]

    The literature on non-genetic peripheral biomarkers for major mental disorders is broad, with conflicting results. An umbrella review of meta-analyses of non-genetic peripheral biomarkers for Alzheimers disease, autism spectrum disorder, bipolar disorder (BD), major depressive disorder, and schizophrenia, including first-episode psychosis. We included meta-analyses that compared alterations in peripheral biomarkers between participants with mental disorders to controls (i.e., between-group meta-analyses) and that assessed biomarkers after treatment (i.e., within-group meta-analyses). Evidence for association was hierarchically graded using a priori defined criteria against several biases. The Assessment of Multiple Systematic Reviews (AMSTAR) instrument was used to investigate study quality. 1161 references were screened. 110 met inclusion criteria, relating to 359 meta-analytic estimates and 733,316 measurements, on 162 different biomarkers. Only two estimates met a priori defined criteria for convincing evidence (elevated awakening cortisol levels in euthymic BD participants relative to controls and decreased pyridoxal levels in participants with schizophrenia relative to controls). Of 42 estimates which met criteria for highly suggestive evidence only five biomarker aberrations occurred in more than one disorder. Only 15 meta-analyses had a power &gt;0.8 to detect a small effect size, and most (81.9%) meta-analyses had high heterogeneity. Although some associations met criteria for either convincing or highly suggestive evidence, overall the vast literature of peripheral biomarkers for major mental disorders is affected by bias and is underpowered. No convincing evidence supported the existence of a trans-diagnostic biomarker. Adequately powered and methodologically sound future large collaborative studies are warranted.

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  • 21.
    Cervenka, Simon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;Stockholm Health Care Services, Region Stockholm, Stockholm, Sweden.
    Frick, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Application of positron emission tomography in psychiatry-methodological developments and future directions2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 248Article in journal (Refereed)
    Abstract [en]

    Mental disorders represent an increasing source of disability and high costs for societies globally. Molecular imaging techniques such as positron emission tomography (PET) represent powerful tools with the potential to advance knowledge regarding disease mechanisms, allowing the development of new treatment approaches. Thus far, most PET research on pathophysiology in psychiatric disorders has focused on the monoaminergic neurotransmission systems, and although a series of discoveries have been made, the results have not led to any material changes in clinical practice. We outline areas of methodological development that can address some of the important obstacles to fruitful progress. First, we point towards new radioligands and targets that can lead to the identification of processes upstream, or parallel to disturbances in monoaminergic systems. Second, we describe the development of new methods of PET data quantification and PET systems that may facilitate research in psychiatric populations. Third, we review the application of multimodal imaging that can link molecular imaging data to other aspects of brain function, thus deepening our understanding of disease processes. Fourth, we highlight the need to develop imaging study protocols to include longitudinal and interventional paradigms, as well as frameworks to assess dimensional symptoms such that the field can move beyond cross-sectional studies within current diagnostic boundaries. Particular effort should be paid to include also the most severely ill patients. Finally, we discuss the importance of harmonizing data collection and promoting data sharing to reach the desired sample sizes needed to fully capture the phenotype of psychiatric conditions.

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  • 22.
    Cervenka, Simon
    et al.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden..
    Hedman, E.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden.;Karolinska Inst, Osher Ctr Integrat Med, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Inst, Div Psychol, Stockholm, Sweden..
    Ikoma, Y.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden.;Natl Inst Radiol Sci, Mol Imaging Ctr, Chiba 260, Japan..
    Djurfeldt, D. Radu
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden..
    Ruck, C.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden..
    Halldin, C.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden..
    Lindefors, N.
    Karolinska Univ, Hosp Solna, Karolinska Inst, Dept Clin Neurosci,Div Psychiat, S-17176 Stockholm, Sweden..
    Changes in dopamine D2-receptor binding are associated to symptom reduction after psychotherapy in social anxiety disorder2012In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 2, article id e120Article in journal (Refereed)
    Abstract [en]

    The dopamine system has been suggested to play a role in social anxiety disorder (SAD), partly based on molecular imaging studies showing reduced levels of striatal dopaminergic markers in patients compared with control subjects. However, the dopamine system has not been examined in frontal and limbic brain regions proposed to be central in the pathophysiology of SAD. In the present study, we hypothesized that extrastriatal dopamine D2-receptor (D2-R) levels measured using positron emission tomography (PET) would predict symptom reduction after cognitive behavior therapy (behavior). Nine SAD patients were examined using high-resolution PET and the high-affinity D2-R antagonist radioligand [C-11]FLB 457, before and after 15 weeks of CBT. Symptom levels were assessed using the anxiety subscale of Liebowitz Social Anxiety Scale (LSAS(anx)). At posttreatment, there was a statistically significant reduction of social anxiety symptoms (Po0.005). Using a repeated measures analysis of covariance, significant effects for time and time x LSAS(anx) change on D2-R-binding potential (BPND) were shown (P<0.05). In a subsequent region-by-region analysis, negative correlations between change in D2-R BPND and LSAS(anx) change were found for medial prefrontal cortex and hippocampus (P<0.05). This is the first study to report a direct relationship between symptom change after psychological treatment and a marker of brain P<0.05. Using an intra-individual comparison design, the study supports a role for the dopamine system in cortical and limbic brain regions in the pathophysiology of SAD. Translational Psychiatry (2012) 2, e120; doi:10.1038/tp.2012.40; published online 22 May 2012

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  • 23.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Boström, Adrian E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Philipps, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Titova, Olga E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Nikontovic, Lamia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1002Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.

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  • 24.
    Cosgrave, Jan
    et al.
    Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Department of Clinical, Educational and Health Psychology, University College London, London, United Kingdom.
    Purple, Ross J.
    Department of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, United Kingdom.
    Haines, Ross
    Department of Statistics, University of Oxford, South Parks Road, Oxford, United Kingdom.
    Porcheret, Kate
    Norwegian Centre for Violence & Traumatic Stress Studies, University of Oslo, Oslo, Norway.
    van Heugten-van der Kloet, Dalena
    Department of Clinical Psychological Science, Maastricht University, Maastricht University, Maastricht, Netherlands.
    Johns, Louise
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom; Oxford Health National Health Service (NHS) Foundation Trust, Oxford, United Kingdom.
    Alexander, Iona
    Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
    Goodwin, Guy M.
    Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, United Kingdom; Oxford Health National Health Service (NHS) Foundation Trust, Oxford, United Kingdom.
    Foster, Russell G.
    Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
    Wulff, Katharina
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Do environmental risk factors for the development of psychosis distribute differently across dimensionally assessed psychotic experiences?2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 226Article in journal (Refereed)
    Abstract [en]

    Psychotic experiences (PE) are associated with poorer functioning, higher distress and the onset of serious mental illness. Environmental exposures (e.g. childhood abuse) are associated with the development of PE. However, which specific exposures convey risk for each type or dimension of PE has rarely been explored. The Oxford Wellbeing Life and Sleep (OWLS) survey includes 22 environmental risk factors for psychosis and was designed to examine how environmental risks are associated with specific dimensions of PE. Multivariate logistic regression models were fit using these risk factors to predict six dimensions of PE (perceptual abnormalities, persecutory ideation, bizarre ideas, cognitive disorganisation, delusional mood and negative symptoms). Models were built using only 70% of the data, and then fit to the remaining data to assess their generalisability and quality. 1789 (27.2% men; mean age = 27.6; SD = 10.9) survey responses were analysed. The risk factors predictive of the most PE were anxiety, social withdrawal during childhood and trauma. Cannabis and depression predicted three dimensions with both predicting bizarre ideas and persecutory ideation. Psychological abuse and sleep quality each predicted two dimensions (persecutory ideation and delusional mood). Risk factors predicting one PE dimension were age (predicting cognitive disorganisation), physical abuse (bizarre ideas), bullying and gender (persecutory ideation); and circadian phase (delusional mood). These results lend support for a continuum of psychosis, suggesting environmental risks for psychotic disorders also increase the risk of assorted dimensions of PE. Furthermore, it advocates the use of dimensional approaches when examining environmental exposures for PE given that environmental risks distribute differently across dimensions.

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  • 25.
    Dubol, Manon
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Neuropsychopharmacology.
    Stiernman, Louise
    Umeå Univ, Dept Clin Sci, S-90185 Umeå, Sweden..
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lanzenberger, Rupert
    Med Univ Vienna, Dept Psychiat & Psychotherapy, A-1090 Vienna, Austria..
    Neill Epperson, C.
    Univ Colorado, Dept Psychiat, Dept Family Med, Sch Med, Anschutz Med Campus, Aurora, CO 80045 USA..
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health.
    Bixo, Marie
    Umeå Univ, Dept Clin Sci, S-90185 Umeå, Sweden..
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 250Article in journal (Refereed)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual-5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen's d = 0.45-0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen's d = 0.34-0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen's d = 0.20-0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

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  • 26.
    Dubol, Manon
    et al.
    Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Stiernman, Louise
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Wikström, Johan
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Lanzenberger, Rupert
    Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
    Neill Epperson, C.
    Department of Psychiatry, Department of Family Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, CO, Aurora, United States.
    Sundström-Poromaa, Inger
    Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Comasco, Erika
    Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 250Article in journal (Refereed)
    Abstract [en]

    Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual—5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen’s d = 0.45–0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen’s d = 0.34–0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen’s d = 0.20–0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

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  • 27.
    Endres, Dominique
    et al.
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy,Sect Expt Neuropsyc, Freiburg, Germany.;Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Pollak, Thomas A.
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Psychosis Studies, London, England..
    Bechter, Karl
    Ulm Univ, Dept Psychiat & Psychotherapy 2, Bezirkskrankenhaus Gunzburg, Gunzburg, Germany..
    Denzel, Dominik
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Pitsch, Karoline
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Nickel, Kathrin
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy,Sect Expt Neuropsyc, Freiburg, Germany.;Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Runge, Kimon
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy,Sect Expt Neuropsyc, Freiburg, Germany.;Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Pankratz, Benjamin
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Klatzmann, David
    Hop La Pitie Salpetriere, AP HP, Biotherapy CIC BTi, Paris, France.;Inflammat Immunopathol Biotherapy Dept i2B, Paris, France.;Sorbonne Univ, Immunol Immunopathol Immunotherapy i3, INSERM, Paris, France..
    Tamouza, Ryad
    Univ Paris Est Creteil, AP HP, FHU ADAPT, DMU IMPACT,Fdn FondaMental,INSERM,IMRB,Translat N, Creteil, France..
    Mallet, Luc
    Univ Paris Est Creteil, AP HP, FHU ADAPT, DMU IMPACT,Fdn FondaMental,INSERM,IMRB,Translat N, Creteil, France..
    Leboyer, Marion
    Univ Paris Est Creteil, AP HP, FHU ADAPT, DMU IMPACT,Fdn FondaMental,INSERM,IMRB,Translat N, Creteil, France..
    Pruess, Harald
    Charite Univ Med Berlin, Dept Neurol & Expt Neurol, Berlin, Germany.;German Ctr Neurodegenerat Dis DZNE Berlin, Berlin, Germany..
    Voderholzer, Ulrich
    Schoen Clin Roseneck, Prien Am Chiemsee, Germany.;Univ Hosp Munich, Dept Psychiat & Psychotherapy, Munich, Germany..
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Domschke, Katharina
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany.;Univ Freiburg, Fac Med, Ctr Basics Neuromodulat, Freiburg, Germany..
    van Elst, Ludger Tebartz
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy,Sect Expt Neuropsyc, Freiburg, Germany.;Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Schiele, Miriam A.
    Univ Freiburg, Med Ctr, Fac Med, Dept Psychiat & Psychotherapy, Freiburg, Germany..
    Immunological causes of obsessive-compulsive disorder: is it time for the concept of an "autoimmune OCD" subtype?2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 5Article, review/survey (Refereed)
    Abstract [en]

    Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of "autoimmune OCD" is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for "autoimmune OCD" could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

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  • 28.
    Fanelli, Giuseppe
    et al.
    Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy.;Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Franke, Barbara
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Psychiat, Nijmegen, Netherlands..
    De Witte, Ward
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Ruisch, I. Hyun
    Univ Groningen, Univ Med Ctr Groningen, Dept Child & Adolescent Psychiat, Groningen, Netherlands..
    Haavik, Jan
    Univ Bergen, Dept Biomed, Bergen, Norway.;Haukeland Hosp, Div Psychiat, Bergen, Norway..
    van Gils, Veerle
    Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands..
    Jansen, Willemijn J.
    Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands..
    Vos, Stephanie J. B.
    Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, Maastricht, Netherlands..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Buitelaar, Jan K.
    Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, Nijmegen, Netherlands..
    Banaschewski, Tobias
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany..
    Dalsgaard, Soren
    Aarhus Univ, Natl Ctr Register Based Res, Aarhus, Denmark.;Lundbeck Fdn Initiat Integrat Psychiat Res, PSYCH, Aarhus, Denmark..
    Serretti, Alessandro
    Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy..
    Mota, Nina Roth
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Poelmans, Geert
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Bralten, Janita
    Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands..
    Insulinopathies of the brain?: Genetic overlap between somatic insulin-related and neuropsychiatric disorders2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 59Article in journal (Refereed)
    Abstract [en]

    The prevalence of somatic insulinopathies, like metabolic syndrome (MetS), obesity, and type 2 diabetes mellitus (T2DM), is higher in Alzheimer's disease (AD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Dysregulation of insulin signalling has been implicated in these neuropsychiatric disorders, and shared genetic factors might partly underlie this observed multimorbidity. We investigated the genetic overlap between AD, ASD, and OCD with MetS, obesity, and T2DM by estimating pairwise global genetic correlations using the summary statistics of the largest available genome-wide association studies for these phenotypes. Having tested these hypotheses, other potential brain "insulinopathies" were also explored by estimating the genetic relationship of six additional neuropsychiatric disorders with nine insulin-related diseases/traits. Stratified covariance analyses were then performed to investigate the contribution of insulin-related gene sets. Significant negative genetic correlations were found between OCD and MetS (r(g) = -0.315, p = 3.9 x 10(-8)), OCD and obesity (r(g) = -0.379, p = 3.4 x 10(-5)), and OCD and T2DM (r(g) = -0.172, p = 3 x 10(-4)). Significant genetic correlations with insulin-related phenotypes were also found for anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and schizophrenia (p < 6.17 x 10(-4)). Stratified analyses showed negative genetic covariances between AD, ASD, OCD, ADHD, AN, bipolar disorder, schizophrenia and somatic insulinopathies through gene sets related to insulin signalling and insulin receptor recycling, and positive genetic covariances between AN and T2DM, as well as ADHD and MetS through gene sets related to insulin processing/secretion (p < 2.06 x 10(-4)). Overall, our findings suggest the existence of two dusters of neuropsychiatric disorders, in which the genetics of insulin-related diseases/traits may exert divergent pleiotropic effects. These results represent a starting point for a new research line on "insulinopathies" of the brain.

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  • 29.
    Farnsworth von Cederwald, Bryn
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Karalija, Nina
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Danish Research Center for Magnetic Resonance (DRCMR), Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Amager and Hvidovre, Copenhagen, Denmark; Institute of Sports Medicine Copenhagen (ISMC) and Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark; Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 28Article in journal (Refereed)
    Abstract [en]

    Age-related dopamine reductions have been suggested to contribute to maladaptive working memory (WM) function in older ages. One promising intervention approach is to increase physical activity, as this has been associated with plasticity of the striatal dopamine system and WM improvements, however with individual differences in efficacy. The present work focused on the impact of individual differences in white-matter lesion burden upon dopamine D2-like receptor (DRD2) availability and WM changes in response to a 6 months physical activity intervention. While the intervention altered striatal DRD2 availability and WM performance in individuals with no or only mild lesions (p < 0.05), no such effects were found in individuals with moderate-to-severe lesion severity (p > 0.05). Follow-up analyses revealed a similar pattern for processing speed, but not for episodic memory performance. Linear analyses further revealed that lesion volume (ml) at baseline was associated with reduced DRD2 availability (r = −0.41, p < 0.05), and level of DRD2 change (r = 0.40, p < 0.05). Taken together, this study underlines the necessity to consider cerebrovascular health in interventions with neurocognitive targets. Future work should assess whether these findings extend beyond measures of DRD2 availability and WM.

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  • 30.
    Fazel, Seena
    et al.
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Wolf, Achim
    Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mallett, Susan
    School of Population and Health Sciences, University of Birmingham, Birmingham, UK.
    Fanshawe, Thomas R.
    Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
    The prediction of suicide in severe mental illness: development and validation of a clinical prediction rule (OxMIS)2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    Assessment of suicide risk in individuals with severe mental illness is currently inconsistent, and based on clinical decision-making with or without tools developed for other purposes. We aimed to develop and validate a predictive model for suicide using data from linked population-based registers in individuals with severe mental illness. A national cohort of 75,158 Swedish individuals aged 15-65 with a diagnosis of severe mental illness (schizophrenia-spectrum disorders, and bipolar disorder) with 574,018 clinical patient episodes between 2001 and 2008, split into development (58,771 patients, 494 suicides) and external validation (16,387 patients, 139 suicides) samples. A multivariable derivation model was developed to determine the strength of pre-specified routinely collected socio-demographic and clinical risk factors, and then tested in external validation. We measured discrimination and calibration for prediction of suicide at 1 year using specified risk cut-offs. A 17-item clinical risk prediction model for suicide was developed and showed moderately good measures of discrimination (c-index 0.71) and calibration. For risk of suicide at 1 year, using a pre-specified 1% cut-off, sensitivity was 55% (95% confidence interval [CI] 47-63%) and specificity was 75% (95% CI 74-75%). Positive and negative predictive values were 2% and 99%, respectively. The model was used to generate a simple freely available web-based probability-based risk calculator (Oxford Mental Illness and Suicide tool or OxMIS) without categorical cut-offs. A scalable prediction score for suicide in individuals with severe mental illness is feasible. If validated in other samples and linked to effective interventions, using a probability score may assist clinical decision-making.

  • 31.
    Frick, A
    et al.
    Uppsala Universitet.
    Howner, K
    Karolinska Institutet.
    Fischer, Håkan
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Kristiansson, M
    Karolinska Institutet.
    Furmark, T
    Uppsala Universitet.
    Altered fusiform connectivity during processing of fearful faces in social anxiety disorder2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, p. e312-Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.

  • 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, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Howner, K
    Fischer, H
    Kristiansson, M
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Altered fusiform connectivity during processing of fearful faces in social anxiety disorder2013In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 3, p. e312-Article in journal (Refereed)
    Abstract [en]

    Social anxiety disorder (SAD) has been associated with hyper-reactivity in limbic brain regions like the amygdala, both during symptom provocation and emotional face processing tasks. In this functional magnetic resonance imaging study we sought to examine brain regions implicated in emotional face processing, and the connectivity between them, in patients with SAD (n=14) compared with healthy controls (n=12). We furthermore aimed to relate brain reactivity and connectivity to self-reported social anxiety symptom severity. SAD patients exhibited hyper-reactivity in the bilateral fusiform gyrus in response to fearful faces, as well as greater connectivity between the fusiform gyrus and amygdala, and decreased connectivity between the fusiform gyrus and ventromedial prefrontal cortex. Within the SAD group, social anxiety severity correlated positively with amygdala reactivity to emotional faces, amygdala-fusiform connectivity and connectivity between the amygdala and superior temporal sulcus (STS). These findings point to a pivotal role for the fusiform gyrus in SAD neuropathology, and further suggest that altered amygdala-fusiform and amygdala-STS connectivity could underlie previous findings of aberrant socio-emotional information processing in this anxiety disorder.

  • 34.
    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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  • 35.
    Garcia-Argibay, Miguel
    et al.
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    du Rietz, Ebba
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lu, Yi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Martin, Joanna
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
    Haan, Elis
    Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
    Letho, Kelli
    Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
    Bergen, Sarah E.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Lichtenstein, Paul
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Henrik
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Brikell, Isabell
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    The role of ADHD genetic risk in mid-to-late life somatic health conditions2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 152Article in journal (Refereed)
    Abstract [en]

    Growing evidence suggests that ADHD, an early onset neurodevelopmental disorder, is associated with poor somatic health in adulthood. However, the mechanisms underlying these associations are poorly understood. Here, we tested whether ADHD polygenic risk scores (PRS) are associated with mid-to-late life somatic health in a general population sample. Furthermore, we explored whether potential associations were moderated and mediated by life-course risk factors. We derived ADHD-PRS in 10,645 Swedish twins born between 1911 and 1958. Sixteen cardiometabolic, autoimmune/inflammatory, and neurological health conditions were evaluated using self-report (age range at measure 42-88 years) and clinical diagnoses defined by International Classification of Diseases codes in national registers. We estimated associations of ADHD-PRS with somatic outcomes using generalized estimating equations, and tested moderation and mediation of these associations by four life-course risk factors (education level, body mass index [BMI], tobacco use, alcohol misuse). Results showed that higher ADHD-PRS were associated with increased risk of seven somatic outcomes (heart failure, cerebro- and peripheral vascular disease, obesity, type 1 diabetes, rheumatoid arthritis, and migraine) with odds ratios ranging 1.07 to 1.20. We observed significant mediation effects by education, BMI, tobacco use, and alcohol misuse, primarily for associations of ADHD-PRS with cardiometabolic outcomes. No moderation effects survived multiple testing correction. Our findings suggests that higher ADHD genetic liability confers a modest risk increase for several somatic health problems in mid-to-late life, particularly in the cardiometabolic domain. These associations were observable in the general population, even in the absence of medical treatment for ADHD, and appear to be in part mediated by life-course risk factors.

  • 36.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Eating Disorders Ctr La Cura Girasole ONLUS, Via Gregorio 7,186-B, I-00165 Rome, Italy;Univ Campus Biomed Roma, Departmental Fac Med & Surg, Area Diagnost Imaging, Via Alvaro del Portillo 200, I-00133 Rome, Italy.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Zobel, Bruno Beomonte
    Univ Campus Biomed Roma, Departmental Fac Med & Surg, Area Diagnost Imaging, Via Alvaro del Portillo 200, I-00133 Rome, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Altered cerebellar-insular-parietal-cingular subnetwork in adolescents in the earliest stages of anorexia nervosa: a network-based statistic analysis2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, article id 127Article in journal (Refereed)
    Abstract [en]

    To date, few functional magnetic resonance imaging (fMRI) studies have explored resting-state functional connectivity (RSFC) in long-lasting anorexia nervosa (AN) patients via graph analysis. The aim of the present study is to investigate, via a graph approach (i.e., the network-based statistic), RSFC in a sample of adolescents at the earliest stages of AN (i.e., AN duration less than 6 months). Resting-state fMRI data was obtained from 15 treatment-naive female adolescents with AN restrictive type (AN-r) in its earliest stages and 15 age-matched healthy female controls. A network-based statistic analysis was used to isolate networks of interconnected nodes that differ between the two groups. Group comparison showed a decreased connectivity in a sub-network of connections encompassing the left and right rostral ACC, left paracentral lobule, left cerebellum (10th sub-division), left posterior insula, left medial fronto-orbital gyrus, and right superior occipital gyrus in AN patients. Results were not associated to alterations in intranodal or global connectivity. No sub-networks with an increased connectivity were identified in AN patients. Our findings suggest that RSFC may be specifically affected at the earliest stages of AN. Considering that the altered sub-network comprises areas mainly involved in somatosensory and interoceptive information and processing and in emotional processes, it could sustain abnormal integration of somatosensory and homeostatic signals, which may explain body image disturbances in AN. Further studies with larger samples and longitudinal designs are needed to confirm our findings and better understand the role and consequences of such functional alterations in AN.

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  • 37.
    Gurholt, Tiril P.
    et al.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Kaufmann, Tobias
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Tubingen, Germany.
    Frei, Oleksandr
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Alnaes, Dag
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Haukvik, Unn K.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    van der Meer, Dennis
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Maastricht Univ, Netherlands.
    Moberget, Torgeir
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Oslo, Norway.
    OConnell, Kevin S.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. AMRA Med, Linkoping, Sweden.
    Linge, Jennifer
    AMRA Med, Linkoping, Sweden.
    Simon, Rozalyn
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. AMRA Med, Linkoping, Sweden.
    Smeland, Olav B.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Sonderby, Ida E.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Oslo Univ Hosp, Norway.
    Winterton, Adriano
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Steen, Nils Eiel
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Westlye, Lars T.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Oslo, Norway.
    Andreassen, Ole A.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Population-based body-brain mapping links brain morphology with anthropometrics and body composition2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 295Article in journal (Refereed)
    Abstract [en]

    Understanding complex body-brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n=24,728) and body MRI (n=4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body-brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body-brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.

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  • 38. Hagg, S.
    et al.
    Zhan, Y.
    Karlsson, R.
    Gerritsen, L.
    Ploner, A.
    van der Lee, S. J.
    Broer, L.
    Deelen, J.
    Marioni, R. E.
    Wong, A.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Zhu, G.
    Hansell, N. K.
    Sillanpaa, E.
    Fedko, I. O.
    Amin, N. A.
    Beekman, M.
    de Craen, A. J. M.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harris, S. E.
    Kan, K-J
    Martin-Ruiz, C. M.
    Montgomery, G. W.
    Adolfsson, Annelie N.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Reynolds, C. A.
    Samani, N. J.
    Suchiman, H. E. D.
    Viljanen, A.
    von Zglinicki, T.
    Wright, M. J.
    Hottenga, J-J
    Boomsma, D. I.
    Rantanen, T.
    Kaprio, J. A.
    Nyholt, D. R.
    Martin, N. G.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Kuh, D.
    Starr, J. M.
    Deary, I. J.
    Slagboom, P. E.
    van Duijn, C. M.
    Codd, V.
    Pedersen, N. L.
    Short telomere length is associated with impaired cognitive performance in European ancestry cohorts2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1100Article in journal (Refereed)
    Abstract [en]

    The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

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  • 39.
    Hallgren, Mats
    et al.
    Karolinska institutet, Stockholm, Sweden.
    Nguyen, Thi-Thuy-Dung
    Karolinska institutet, Stockholm, Sweden.
    Owen, Neville
    Swinburne University of Technology, Melbourne, Australia.
    Vancampfort, Davy
    Katholieke Universiteit Leuven, Leuven, Belgium.
    Smith, Lee
    Anglia Ruskin University, Cambridge, UK.
    Dunstan, David W
    Australian Catholic University, Melbourne, Australia..
    Andersson, Gunnar
    HPI Health Profile Institute, Danderyd, Sweden.
    Wallin, Peter
    HPI Health Profile Institute, Danderyd, Sweden.
    Ekblom Bak, Elin
    Swedish School of Sport and Health Sciences, GIH, Department of Sport and Health Sciences, Åstrand Laboratory of Work Physiology.
    Associations of interruptions to leisure-time sedentary behaviour with symptoms of depression and anxiety.2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1, article id 128Article in journal (Refereed)
    Abstract [en]

    Interruptions to time spent sitting can ameliorate detrimental metabolic-health consequences of high volumes of sedentary time, but their potential mental health benefits have not been examined. We used the Swedish Health Profile Assessment database, a general health assessment offered to all employees working for companies or organisations connected to occupational and health services. Cross-sectional analyses examined data from 40,550 employees (60% male, mean age = 42 years), collected in 2017-2019. Participants reported the proportion of time (almost always; 75% of the time; 50% of the time; 25% of the time; and almost never) usually spent in leisure-time sedentary behaviours; and, separately, the frequency (never; rarely; sometimes; often; and very often) of interruptions (every 30 min) to sedentary time. Logistic regression models assessed associations of sedentary time, and the frequency of interruptions to sedentary time, with depression/anxiety symptoms. Fully adjusted models included physical exercise. Compared to those in the lowest sedentary time category, those in the medium and high categories had 1.52 (95% confidence interval (CI) = 1.40-1.66) and 3.11 (95% CI = 2.82-3.42) higher odds of frequent depression/anxiety symptoms, respectively. Compared to those who never/rarely interrupted their sedentary time, those who reported interruptions sometimes, often and very often had 0.72 (95% CI = 0.65-0.80), 0.59 (95% CI = 0.53-0.65), and 0.53 (95% CI = 0.46-0.59) lower odds of depression/anxiety symptoms, respectively. In stratified analyses, more frequent interruptions to sedentary time were associated with lower odds of depression/anxiety symptoms, except among those in the lowest interruptions categories (never/25% of the time). More regularly interrupting sitting during leisure-time may reduce the odds of experiencing symptoms of depression and anxiety.

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  • 40.
    Hamilton, Paul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Sacchet, Matthew D.
    Stanford Univ, CA 94305 USA.
    Hjornevik, Trine
    Oslo Univ Hosp, Norway; Norwegian Med Cyclotron Ctr, Norway; Stanford Univ, CA 94305 USA.
    Chin, Frederick T.
    Stanford Univ, CA 94305 USA.
    Shen, Bin
    Stanford Univ, CA 94305 USA.
    Kämpe, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Park, Jun Hyung
    Stanford Univ, CA 94305 USA.
    Knutson, Brian D.
    Stanford Univ, CA USA.
    Williams, Leanne M.
    Stanford Univ, CA 94305 USA.
    Borg, Nicholas
    Stanford Univ, CA USA.
    Zaharchuk, Greg
    Stanford Univ, CA 94305 USA.
    Camacho, M. Catalina
    Univ Pittsburgh, PA 15260 USA.
    Mackey, Sean
    Stanford Univ, CA 94305 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Drevets, Wayne C.
    Janssen Res and Dev LLC, NJ USA.
    Glover, Gary H.
    Stanford Univ, CA 94305 USA.
    Gambhir, Sanjiv S.
    Stanford Univ, CA 94305 USA.
    Gotlib, Ian H.
    Stanford Univ, CA USA.
    Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent C-11-raclopride positron emission tomography and functional magnetic resonance imaging investigation2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, article id 264Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the corticostriatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and C-11-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and C-11-raclopride PET. We estimated raclopride binding potential (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.

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  • 41.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Pfarr, Simone
    Cent Inst Mental Hlth, Germany.
    Sommer, Wolfgang H.
    Cent Inst Mental Hlth, Germany; Cent Inst Mental Hlth, Germany.
    Developing neuroscience-based treatments for alcohol addiction: A matter of choice?2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 255Article, review/survey (Refereed)
    Abstract [en]

    Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for -5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with "alcohol dependence" or simply "alcoholism"), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences ("compulsivity"). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.

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  • 42.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Han, L K M
    Connolly, C G
    Ho, T C
    Lin, J
    LeWinn, K Z
    Simmons, A N
    Sacchet, M D
    Mobayed, N
    Luna, M E
    Paulus, M
    Epel, E S
    Blackburn, E H
    Wolkowitz, O M
    Yang, T T
    Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, article id e676Article in journal (Refereed)
    Abstract [en]

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

  • 43.
    Henriksson, Hanna E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Malavaki, Christina
    Metabolic Engineering & Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece.
    Bränn, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Drainas, Vasilis
    Metabolic Engineering & Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece; Department of Chemical Engineering, University of Patras, Patras, Greece .
    Lager, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Iliadis, Stavros I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Papadopoulos, Fotios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Chrousos, George P.
    First Department of Pediatrics, Athens University Medical School, Athens, Greece.
    Klapa, Maria I.
    Metabolic Engineering & Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Blood plasma metabolic profiling of pregnant women with antenatal depressive symptoms2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 204Article in journal (Refereed)
    Abstract [en]

    Antenatal depression affects similar to 9-19% of pregnant women and can exert persistent adverse effects on both mother and child. There is a need for a deeper understanding of antenatal depression mechanisms and the development of tools for reliable diagnosis and early identification of women at high risk. As the use of untargeted blood metabolomics in the investigation of psychiatric and neurological diseases has increased substantially, the main objective of this study was to investigate whether untargeted gas chromatography-mass spectrometry (GC-MS) plasma metabolomics in 45 women in late pregnancy, residing in Uppsala, Sweden, could indicate metabolic differences between women with and without depressive symptoms. Furthermore, seasonal differences in the metabolic profiles were explored. When comparing the profiles of cases with controls, independently of season, no differences were observed. However, seasonal differences were observed in the metabolic profiles of control samples, suggesting a favorable cardiometabolic profile in the summer vs. winter, as indicated by lower glucose and sugar acid concentrations and lactate to pyruvate ratio, and higher abundance of arginine and phosphate. Similar differences were identified between cases and controls among summer pregnancies, indicating an association between a stressed metabolism and depressive symptoms. No depression-specific differences were apparent among depressed and non-depressed women, in the winter pregnancies; this could be attributed to an already stressed metabolism due to the winter living conditions. Our results provide new insights into the pathophysiology of antenatal depression, and warrant further investigation of the use of metabolomics in antenatal depression in larger cohorts.

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  • 44.
    Hidalgo-Lopez, Esmeralda
    et al.
    Univ Salzburg, Dept Psychol, Salzburg, Austria.;Univ Salzburg, Ctr Cognit Neurosci, Salzburg, Austria.;Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA.;Univ Michigan, Chron Pain & Fatigue Res Ctr, Dept Anesthesiol, Ann Arbor, MI 48109 USA..
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Poromaa, Inger Sundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Reproductive Health. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    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 Women's and Children's Health, Reproductive Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    Pletzer, Belinda
    Univ Salzburg, Dept Psychol, Salzburg, Austria.;Univ Salzburg, Ctr Cognit Neurosci, Salzburg, Austria..
    Triple network model of brain connectivity changes related to adverse mood effects in an oral contraceptive placebo-controlled trial2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 209Article in journal (Refereed)
    Abstract [en]

    Combined oral contraceptives (COC) are among the most commonly used contraceptive methods worldwide, and mood side effects are the major reason for discontinuation of treatment. We here investigate the directed connectivity patterns associated with the mood side effects of an androgenic COC in a double-blind randomized, placebo-controlled trial in women with a history of affective COC side effects (n = 34). We used spectral dynamic causal modeling on a triple network model consisting of the default mode network (DMN), salience network (SN) and executive control network (ECN). Within this framework, we assessed the treatment-related changes in directed connectivity associated with adverse mood side effects. Overall, during COC use, we found a pattern of enhanced connectivity within the DMN and decreased connectivity within the ECN. The dorsal anterior cingulate cortex (SN) mediates an increased recruitment of the DMN by the ECN during treatment. Mood lability was the most prominent COC-induced symptom and also arose as the side effect most consistently related to connectivity changes. Connections that were related to increased mood lability showed increased connectivity during COC treatment, while connections that were related to decreased mood lability showed decreased connectivity during COC treatment. Among these, the connections with the highest effect size could also predict the participants' treatment group above chance.

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  • 45.
    Hjorth, Olof
    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 Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Psychiatry.
    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 Medical Sciences, Psychiatry.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Björkstrand, Johannes
    Faria, Vanda
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Child and Adolescent Psychiatry.
    Carlbring, Per
    Andersson, Gerhard
    Jonasson, My
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Reis, Margareta
    Wahlstedt, Kurt
    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, Stockholm, Sweden..
    Furmark, Tomas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, article id 436Article in journal (Refereed)
    Abstract [en]

    Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

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  • 46.
    Hjorth, Olof
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frick, Andreas
    Department of Psychology, Uppsala University and The Beijer Laboratory, Department of Medical Sciences, Psychiatry, Uppsala University, Uppsala, Sweden.
    Gingnell, Malin
    Department of Psychology, Uppsala University and Department of Medical Sciences, Psychiatry, Uppsala University, Uppsala, Sweden.
    Engman, Jonas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Björkstrand, Johannes
    Department of Psychology, Lund University, Lund, Sweden.
    Faria, Vanda
    Center for Pain and the Brain, Department of Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA and Smell & Taste Clinic, Department of Otorhinolaryngology, TU Dresden, Dresden, Germany.
    Alaie, Iman
    Department of Medical Sciences, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden.
    Carlbring, Per
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jonasson, My
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Lubberink, Mark
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Antoni, Gunnar
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Reis, Margareta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlstedt, Kurt
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy.2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 436Article in journal (Refereed)
    Abstract [en]

    Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

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  • 47. Hjorth, Olof
    et al.
    Frick, Andreas
    Gingnell, Malin
    Engman, Jonas
    Björkstrand, Johannes
    Faria, Vanda
    Alaie, Iman
    Carlbring, Per
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology.
    Andersson, Gerhard
    Jonasson, My
    Lubberink, Mark
    Antoni, Gunnar
    Reis, Margareta
    Wahlstedt, Kurt
    Fredrikson, Mats
    Furmark, Tomas
    Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 436Article in journal (Refereed)
    Abstract [en]

    Selective serotonin reuptake inhibitors (SSRIs) and internet-based cognitive behavioral therapy (ICBT) are recommended treatments of social anxiety disorder (SAD), and often combined, but their effects on monoaminergic signaling are not well understood. In this multi-tracer positron emission tomography (PET) study, 24 patients with SAD were randomized to treatment with escitalopram+ICBT or placebo+ICBT under double-blind conditions. Before and after 9 weeks of treatment, patients were examined with positron emission tomography and the radioligands [11C]DASB and [11C]PE2I, probing the serotonin (SERT) and dopamine (DAT) transporter proteins respectively. Both treatment combinations resulted in significant improvement as measured by the Liebowitz Social Anxiety Scale (LSAS). At baseline, SERT-DAT co-expression was high and, in the putamen and thalamus, co-expression showed positive associations with symptom severity. SERT-DAT co-expression was also predictive of treatment success, but predictor-outcome associations differed in direction between the treatments. After treatment, average SERT occupancy in the SSRI + ICBT group was >80%, with positive associations between symptom improvement and occupancy in the nucleus accumbens, putamen and anterior cingulate cortex. Following placebo+ICBT, SERT binding increased in the raphe nuclei. DAT binding increased in both groups in limbic and striatal areas, but relations with symptom improvement differed, being negative for SSRI + ICBT and positive for placebo + ICBT. Thus, serotonin-dopamine transporter co-expression exerts influence on symptom severity and remission rate in the treatment of social anxiety disorder. However, the monoamine transporters are modulated in dissimilar ways when cognitive-behavioral treatment is given concomitantly with either SSRI-medication or pill placebo.

  • 48.
    Hjorth, Olof
    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, Cervenka: Psychiatry. 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, Cervenka: Psychiatry.
    Hoppe, Johanna M.
    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 Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA;Smell & Taste Clinic, Department of Otorhinolaryngology, TU Dresden, Dresden, Germany.
    Hultberg, Sara
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Alaie, Iman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ramklint: Child and Adolescent Psychiatry.
    Månsson, Kristoffer N. T.
    Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden;Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany;Max Planck UCL Center for Computational Psychiatry and Ageing Research, Berlin/London, UK.
    Rosén, Jörgen
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Reis, Margareta
    Department of Biomedical And Clinical Sciences, Linköping University, Linköping, Sweden;Department of Clinical Chemistry and Pharmacology, Skåne University hospital, Lund, Sweden.
    Wahlstedt, Kurt
    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.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal 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.
    Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 559Article in journal (Refereed)
    Abstract [en]

    It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

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  • 49.
    Hjorth, Olof R.
    et al.
    Uppsala Univ, Sweden.
    Frick, Andreas
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Gingnell, Malin
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Hoppe, Johanna M.
    Uppsala Univ, Sweden.
    Faria, Vanda
    Uppsala Univ, Sweden; Harvard Med Sch, MA 02115 USA; Tech Univ Dresden, Germany.
    Hultberg, Sara
    Uppsala Univ, Sweden.
    Alaie, Iman
    Uppsala Univ, Sweden.
    Mansson, Kristoffer N. T.
    Karolinska Inst, Sweden; Max Planck Inst Human Dev, Germany; Max Planck UCL Ctr Computat Psychiat & Ageing Res, England.
    Rosen, Jorgen
    Uppsala Univ, Sweden.
    Reis, Margareta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Skane Univ Hosp, Sweden.
    Wahlstedt, Kurt
    Uppsala Univ, Sweden.
    Jonasson, My
    Uppsala Univ, Sweden.
    Lubberink, Mark
    Uppsala Univ, Sweden.
    Antoni, Gunnar
    Uppsala Univ, Sweden.
    Fredrikson, Mats
    Uppsala Univ, Sweden; Karolinska Inst, Sweden.
    Furmark, Tomas
    Uppsala Univ, Sweden.
    Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 559Article in journal (Refereed)
    Abstract [en]

    It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [C-11]DASB and [C-11]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

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  • 50.
    Holmes, Emily A.
    et al.
    Department for Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Bonsall, M B
    Hales, S A
    Mitchell, H
    Renner, F
    Blackwell, S E
    Watson, P
    Goodwin, G M
    Di Simplicio, M
    Applications of time-series analysis to mood fluctuations in bipolar disorder to promote treatment innovation: a case series.2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, article id e720Article in journal (Refereed)
    Abstract [en]

    Treatment innovation for bipolar disorder has been hampered by a lack of techniques to capture a hallmark symptom: ongoing mood instability. Mood swings persist during remission from acute mood episodes and impair daily functioning. The last significant treatment advance remains Lithium (in the 1970s), which aids only the minority of patients. There is no accepted way to establish proof of concept for a new mood-stabilizing treatment. We suggest that combining insights from mood measurement with applied mathematics may provide a step change: repeated daily mood measurement (depression) over a short time frame (1 month) can create individual bipolar mood instability profiles. A time-series approach allows comparison of mood instability pre- and post-treatment. We test a new imagery-focused cognitive therapy treatment approach (MAPP; Mood Action Psychology Programme) targeting a driver of mood instability, and apply these measurement methods in a non-concurrent multiple baseline design case series of 14 patients with bipolar disorder. Weekly mood monitoring and treatment target data improved for the whole sample combined. Time-series analyses of daily mood data, sampled remotely (mobile phone/Internet) for 28 days pre- and post-treatment, demonstrated improvements in individuals' mood stability for 11 of 14 patients. Thus the findings offer preliminary support for a new imagery-focused treatment approach. They also indicate a step in treatment innovation without the requirement for trials in illness episodes or relapse prevention. Importantly, daily measurement offers a description of mood instability at the individual patient level in a clinically meaningful time frame. This costly, chronic and disabling mental illness demands innovation in both treatment approaches (whether pharmacological or psychological) and measurement tool: this work indicates that daily measurements can be used to detect improvement in individual mood stability for treatment innovation (MAPP).

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