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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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri. 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 disorder2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, nr 1, artikel-id 238Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sarkisyan, Daniil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karpyak, Victor M.
    Mayo Clin, Coll Med, Dept Psychiat & Psychol, Rochester, MN 55905 USA.
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics2018Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, artikel-id 122Artikel i tidskrift (Refereegranskat)
    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.
    Bendre, Megha
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Comasco, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neuropsykofarmakologi.
    Nylander, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nilsson, Kent W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    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 alcohol2015Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, artikel-id e690Artikel i tidskrift (Refereegranskat)
    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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  • 4. Bergman, O.
    et al.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Linnman, Claes
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Faria, Vanda
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Bani, M.
    Pich, E. M.
    Bettica, P.
    Henningsson, S.
    Manuck, S. B.
    Ferrell, R. E.
    Nikolova, Y. S.
    Hariri, A. R.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Westberg, L.
    Eriksson, E.
    Association between amygdala reactivity and a dopamine transporter gene polymorphism2014Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 4, s. e420-Artikel i tidskrift (Refereegranskat)
    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.

  • 5.
    Bodén, Robert
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Persson, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Wall, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Ekselius, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Antoni, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Striatal phosphodiesterase 10A and medial prefrontal cortical thickness in patients with schizophrenia: a PET and MRI study2017Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, nr 3, artikel-id e1050Artikel i tidskrift (Refereegranskat)
    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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  • 6.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    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 disease2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikel-id 55Artikel i tidskrift (Refereegranskat)
    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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  • 7.
    Ciuculete, Diana-Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Boström, Adrian E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Voisin, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Philipps, H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Titova, Olga E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bandstein, Marcus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nikontovic, Lamia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Mwinyi, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score2017Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, artikel-id e1002Artikel i tidskrift (Refereegranskat)
    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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  • 8.
    Frick, Andreas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Howner, K
    Fischer, H
    Kristiansson, M
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Altered fusiform connectivity during processing of fearful faces in social anxiety disorder2013Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 3, s. e312-Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    Frick, Andreas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Linnman, Clas
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Increased neurokinin-1 receptor availability in the amygdala in social anxiety disorder: a positron emission tomography study with [(11)C]GR2051712015Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, artikel-id e597Artikel i tidskrift (Refereegranskat)
    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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  • 10.
    Gaudio, Santino
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Altered cerebellar-insular-parietal-cingular subnetwork in adolescents in the earliest stages of anorexia nervosa: a network-based statistic analysis2018Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, artikel-id 127Artikel i tidskrift (Refereegranskat)
    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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  • 11.
    Henriksson, Hanna E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    Iliadis, Stavros I
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    Papadopoulos, Fotios
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    Blood plasma metabolic profiling of pregnant women with antenatal depressive symptoms2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikel-id 204Artikel i tidskrift (Refereegranskat)
    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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  • 12.
    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.2016Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, artikel-id e720Artikel i tidskrift (Refereegranskat)
    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).

  • 13. Karpyak, V. M.
    et al.
    Biernacka, J. M.
    Geske, J. R.
    Jenkins, G. D.
    Cunningham, J. M.
    Rueegg, J.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Leontovich, A. A.
    Abulseoud, O. A.
    Hall-Flavin, D. K.
    Loukianova, L. L.
    Schneekloth, T. D.
    Skime, M. K.
    Frank, J.
    Noethen, M. M.
    Rietschel, M.
    Kiefer, F.
    Mann, K. F.
    Weinshilboum, R. M.
    Frye, M. A.
    Choi, D. S.
    Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate2014Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 4, s. e462-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P = 4.6 x 10(-5)). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P = 0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P = 0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

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  • 14. Kuzmin, A.
    et al.
    Chefer, V.
    Bazov, Igor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Meis, J.
    Ogren, S. O.
    Shippenberg, T.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment2013Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 3, s. e310-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The dynorphin opioid peptides control glutamate neurotransmission in the hippocampus. Alcohol-induced dysregulation of this circuit may lead to impairments in spatial learning and memory. This study examines whether changes in the hippocampal dynorphin and glutamate systems are related, and contribute to impairment of spatial learning and memory in a rat model of cognitive deficit associated with alcohol binge drinking. Hippocampal dynorphins (radioimmunoassay) and glutamate (in vivo microdialysis) were analyzed in Wistar rats exposed to repeated moderate-dose ethanol bouts that impair spatial learning and memory in the Water Maze Task (WMT). The highly selective, long-acting k-opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI) was administered systemically or into the hippocampal CA3 region to test a role of dynorphins in alcohol-induced dysregulations in glutamate neurotransmission and behavior in the WMT. The ethanol treatment impaired learning and memory, upregulated dynorphins and increased glutamate overflow in the CA3 region. Administration of nor-BNI after cessation of ethanol exposure reversed ethanol-induced changes in glutamate neurotransmission in animals exposed to ethanol and normalized their performance in the WMT. The findings suggest that impairments of spatial learning and memory by binge-like ethanol exposure are mediated through the KOR activation by upregulated dynorphins resulting in elevation in glutamate levels. Selective KOR antagonists may correct alcohol-induced pathological processes, thus representing a novel pharmacotherapy for treating of ethanol-related cognitive deficits.

  • 15.
    Mansson, K. N. T.
    et al.
    Linkoping Univ, Div Psychol, Dept Behav Sci & Learning, SE-58183 Linkoping, Sweden..
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Boraxbekk, C-J
    Umea Univ, Ctr Populat Studies Ageing & Living Condit, Umea, Sweden.;Umea Univ, Umea Ctr Funct Brain Imaging UFBI, Umea, Sweden..
    Marquand, A. F.
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6525 ED Nijmegen, Netherlands.;Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England..
    Williams, S. C. R.
    Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England..
    Carlbring, P.
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden..
    Andersson, G.
    Linkoping Univ, Div Psychol, Dept Behav Sci & Learning, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Stockholm, Sweden..
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning2015Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, artikel-id e530Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cognitive behavior therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but many patients do not respond sufficiently and a substantial proportion relapse after treatment has ended. Predicting an individual's long-term clinical response therefore remains an important challenge. This study aimed at assessing neural predictors of long-term treatment outcome in participants with SAD 1 year after completion of Internet-delivered CBT (iCBT). Twenty-six participants diagnosed with SAD underwent iCBT including attention bias modification for a total of 13 weeks. Support vector machines (SVMs), a supervised pattern recognition method allowing predictions at the individual level, were trained to separate long-term treatment responders from nonresponders based on blood oxygen level-dependent (BOLD) responses to self-referential criticism. The Clinical Global Impression-Improvement scale was the main instrument to determine treatment response at the 1-year follow-up. Results showed that the proportion of long-term responders was 52% (12/23). From multivariate BOLD responses in the dorsal anterior cingulate cortex (dACC) together with the amygdala, we were able to predict long-term response rate of iCBT with an accuracy of 92% (confidence interval 95% 73.2-97.6). This activation pattern was, however, not predictive of improvement in the continuous Liebowitz Social Anxiety Scale-Self-report version. Follow-up psychophysiological interaction analyses revealed that lower dACC-amygdala coupling was associated with better long-term treatment response. Thus, BOLD response patterns in the fear-expressing dACC-amygdala regions were highly predictive of long-term treatment outcome of iCBT, and the initial coupling between these regions differentiated long-term responders from nonresponders. The SVM-neuroimaging approach could be of particular clinical value as it allows for accurate prediction of treatment outcome at the level of the individual.

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  • 16.
    Momeni, N
    et al.
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Brudin, L
    Department of Clinical Physiology, Kalmar County Hospital, Kalmar, Sweden.
    Behnia, F
    Department of Occupational Therapy, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
    Sivberg, B
    Department of Health Sciences, Lund University, Lund, Sweden.
    Joghataei, M T
    Cellular and Molecular Research Centre, Tehran Medical University, Tehran, Iran.
    Persson, B L
    School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
    A novel blood-based biomarker for detection of autism spectrum disorders2012Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 2, artikel-id e91Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autism spectrum disorders (ASD) are classified as neurological developmental disorders. Several studies have been carried out to find a candidate biomarker linked to the development of these disorders, but up to date no reliable biomarker is available. Mass spectrometry techniques have been used for protein profiling of blood plasma of children with such disorders in order to identify proteins/peptides that may be used as biomarkers for detection of the disorders. Three differentially expressed peptides with mass–charge (m/z) values of 2020±1, 1864±1 and 1978±1 Da in the heparin plasma of children with ASD that were significantly changed as compared with the peptide pattern of the non-ASD control group are reported here. This novel set of biomarkers allows for a reliable blood-based diagnostic tool that may be used in diagnosis and potentially, in prognosis of ASD.

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  • 17.
    Motilla Hoppe, Johanna
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Åhs, Fredrik
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Linnman, Clas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Appel, Lieuwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Jonasson, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Långström, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Frans, Örjan
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    von Knorring, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Fredriksson, M
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits2018Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, nr 1, s. 168-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions. Here we examined the relationship between central NK1 receptor availability and self-rated measures of trait anxiety, neuroticism, and extraversion. The amygdala was chosen as the primary region of interest since this structure has been suggested to mediate the effect of the SP-NK1 system on anxiety. Anxious traits and NK1 receptor availability, determined with positron emission tomography and the radiotracer [11C]GR205171, were measured in 17 healthy individuals. Voxel-wise analyses showed a significant positive correlation between bilateral amygdala NK1 receptor availability and trait anxiety, and a trend in similar direction was observed for neuroticism. Conversely, extraversion was found to be negatively associated with amygdala NK1 receptor availability. Extraversion also correlated negatively with the NK1 measure in the cuneus/precuneus and fusiform gyrus according to exploratory whole-brain analyses. In conclusion, our findings indicate that amygdala NK1 receptor availability is associated with anxiety-related personality traits in healthy subjects, consistent with a modulatory role for the SP-NK1 system in human anxiety.

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  • 18. Månsson, K N T
    et al.
    Salami, A
    Frick, Andreas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Carlbring, P
    Andersson, G
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Boraxbekk, C-J
    Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder2016Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, artikel-id e727Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with anxiety disorders exhibit excessive neural reactivity in the amygdala, which can be normalized by effective treatment like cognitive behavior therapy (CBT). Mechanisms underlying the brain's adaptation to anxiolytic treatments are likely related both to structural plasticity and functional response alterations, but multimodal neuroimaging studies addressing structure-function interactions are currently missing. Here, we examined treatment-related changes in brain structure (gray matter (GM) volume) and function (blood-oxygen level dependent, BOLD response to self-referential criticism) in 26 participants with social anxiety disorder randomly assigned either to CBT or an attention bias modification control treatment. Also, 26 matched healthy controls were included. Significant time × treatment interactions were found in the amygdala with decreases both in GM volume (family-wise error (FWE) corrected P(FWE) = 0.02) and BOLD responsivity (P(FWE) = 0.01) after successful CBT. Before treatment, amygdala GM volume correlated positively with anticipatory speech anxiety (P(FWE)=0.04), and CBT-induced reduction of amygdala GM volume (pre-post) correlated positively with reduced anticipatory anxiety after treatment (P(FWE) ⩽ 0.05). In addition, we observed greater amygdala neural responsivity to self-referential criticism in socially anxious participants, as compared with controls (P(FWE) = 0.029), before but not after CBT. Further analysis indicated that diminished amygdala GM volume mediated the relationship between decreased neural responsivity and reduced social anxiety after treatment (P=0.007). Thus, our results suggest that improvement-related structural plasticity impacts neural responsiveness within the amygdala, which could be essential for achieving anxiety reduction with CBT.

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  • 19.
    Månsson, Kristoffer N.T.
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Lindqvist, Daniel
    Yang, Liu L.
    Svanborg, Cecilia
    Isung, Josef
    Nilsonne, Gustav
    Bergman-Nordgren, Lise
    El Alaoui, Samir
    Hedman-Lagerlöf, Erik
    Kraepelien, Martin
    Högström, Jens
    Andersson, Gerhard
    Boraxbekk, Carl-Johan
    Fischer, Håkan
    Lavebratt, Catharina
    Wolkowitz, Owen M.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, nr 1, artikel-id 340Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.

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  • 20.
    Olivo, Gaia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Swenne, Ingemar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnendokrinologisk forskning.
    Zhukovsky, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Tuunainen, Anna-Kaisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Salonen-Ros, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Gaudio, Santino
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi. Univ Campus Biomed Roma, Ctr Integrated Res, Area Diagnost Imaging, Rome, Italy.
    Brooks, Samantha J.
    Univ Cape Town, Dept Human Biol, Cape Town, South Africa.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Reduced resting-state connectivity in areas involved in processing of face-related social cues in female adolescents with atypical anorexia nervosa2018Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, artikel-id 275Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Atypical anorexia nervosa (AN) has a high incidence in adolescents and can result in significant morbidity and mortality. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders (EDs), however research on adolescents with EDs is limited. To date no neuroimaging studies have been conducted to investigate brain functional connectivity in atypical AN. We investigated resting-state functional connectivity using 3 T MRI in 22 drug-naive adolescent patients with atypical AN, and 24 healthy controls. Psychological traits related to the ED and depressive symptoms have been assessed using the Eating Disorders Examination Questionnaire (EDE-Q) and the Montgomery-Asberg Depression Rating Scale self-reported (MADRS-S) respectively. Reduced connectivity was found in patients in brain areas involved in face-processing and social cognition, such as the left putamen, the left occipital fusiform gyrus, and specific cerebellar lobules. The connectivity was, on the other hand, increased in patients compared with controls from the right inferior temporal gyrus to the superior parietal lobule and superior lateral occipital cortex. These areas are involved in multimodal stimuli integration, social rejection and anxiety. Patients scored higher on the EDE-Q and MADRS-S questionnaires, and the MADRS-S correlated with connectivity from the right inferior temporal gyrus to the superior parietal lobule in patients. Our findings point toward a role for an altered development of socio-emotional skills in the pathogenesis of atypical AN. Nonetheless, longitudinal studies will be needed to assess whether these connectivity alterations might be a neural marker of the pathology.

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  • 21.
    Olivo, Gaia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Zhukovsky, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Salonen-Ros, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Barn- och ungdomspsykiatri.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Brooks, Samantha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi. Department of Human Biology, University of Cape Town, Cape Town, South Africa; School of Natural Sciences and Psychology, Research Centre for Brain & Behaviour, Byrom Street, Liverpool, UK.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Functional connectivity underlying hedonic response to food in female adolescents with atypical AN: The role of somatosensory and salience networks2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikel-id 276Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Atypical Anorexia Nervosa (AN) usually occurs during adolescence. Patients are often in the normal-weight range at diagnosis, however they often present with signs of medical complications and severe restraint over eating, body dissatisfaction, and low self-esteem. We investigated functional circuitry underlying the hedonic response in 28 female adolescent patients diagnosed with atypical AN and 33 healthy controls. Participants were shown images of food with high (HC) or low (LC) caloric content in alternating blocks during functional MRI. The HC > LC contrast was calculated. Based on previous literature on full-threshold AN, we hypothesized that patients would exhibit increased connectivity in areas involved in sensory processing and bottom-up responses, coupled to increased connectivity from areas related to top-down inhibitory control, compared with controls. Patients showed increased connectivity in pathways related to multimodal somatosensory processing and memory retrieval. The connectivity was on the other hand decreased in patients in salience and attentional networks, and in a wide cerebello-occipital network. Our study was the first investigation of food-related neural response in atypical AN. Our findings support higher somatosensory processing in patients in response to HC food images compared with controls, however HC food was less efficient than LC food in engaging patients’ bottom-up salient responses, and was not associated with connectivity increases in inhibitory control regions. These findings suggest that the psychopathological mechanisms underlying food restriction in atypical AN differ from full-threshold AN. Elucidating the mechanisms underlying the development and maintenance of eating behaviour in atypical AN might help designing specific treatment strategies.

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  • 22.
    Pisanu, Claudia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Williams, Michael J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Ciuculete, Diana-Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Olivo, Gaia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Del Zompo, Maria
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Evidence that genes involved in hedgehog signaling are associated with both bipolar disorder and high BMI2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikel-id 315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with bipolar disorder (BD) show higher frequency of obesity and type 2 diabetes (T2D), but the underlying genetic determinants and molecular pathways are not well studied. Using large publicly available datasets, we (1) conducted a gene-based analysis using MAGMA to identify genes associated with BD and body mass index (BMI) or T2D and investigated their functional enrichment; and (2) performed two meta-analyses between BD and BMI, as well as BD and T2D using Metasoft. Target druggability was assessed using the Drug Gene Interaction Database (DGIdb). We identified 518 and 390 genes significantly associated with BD and BMI or BD and T2D, respectively. A total of 52 and 12 genes, respectively, were significant after multiple testing correction. Pathway analyses conducted on nominally significant targets showed that genes associated with BD and BMI were enriched for the Neuronal cell body Gene Ontology (GO) term (p = 1.0E-04; false discovery rate (FDR) = 0.025) and different pathways, including the Signaling by Hedgehog pathway (p = 4.8E -05, FDR = 0.02), while genes associated with BD and T2D showed no specific enrichment. The meta-analysis between BD and BMI identified 64 relevant single nucleotide polymorphisms (SNPs). While the majority of these were located in intergenic regions or in a locus on chromosome 16 near and in the NPIPL1 and SH2B1 genes (best SNP: rs4788101, p = 2.1E-24), five were located in the ETV5 gene (best SNP: rs1516725, p= 1E-24), which was previously associated with both BD and obesity, and one in the RPGRIP1L gene (rs1477199, p = 5.7E-09), which was also included in the Signaling by Hedgehog pathway. The meta-analysis between BD and T2D identified six significant SNPs, three of which were located in ALAS1 (best SNP: rs352165, p = 3.4E-08). Thirteen SNPs associated with BD and BMI, and one with BD and T2D, were located in genes which are part of the druggable genome. Our results support the hypothesis of shared genetic determinants between BD and BMI and point to genes involved in Hedgehog signaling as promising targets.

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  • 23.
    Porcheret, Kate
    et al.
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford OX1 3RE, England.
    van Heugten-van der Kloet, Dalena
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford OX1 3RE, England;Maastricht Univ, Fac Psychol & Neurosci, Dept Clin Psychol Sci, NL-6200 MD Maastricht, Netherlands.
    Goodwin, Guy M.
    Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England;Oxford Hlth NHS Fdn Trust, Oxford OX3 7JX, England.
    Foster, Russell G.
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford OX1 3RE, England.
    Wulff, Katharina
    Univ Oxford, Sleep & Circadian Neurosci Inst, Nuffield Dept Clin Neurosci, Oxford OX1 3RE, England;Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden;Umea Univ, Dept Mol Biol, SE-90187 Umea, Sweden.
    Holmes, Emily A.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Investigation of the impact of total sleep deprivation at home on the number of intrusive memories to an analogue trauma2019Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, artikel-id 104Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sleep enhances the consolidation of memory; however, this property of sleep may be detrimental in situations where memories of an event can lead to psychopathology, such as following a traumatic event. Intrusive memories of trauma are emotional memories that spring to mind involuntarily and are a core feature of post-traumatic stress disorder. Total sleep deprivation in a hospital setting on the first night after an analogue trauma (a trauma film) led to fewer intrusive memories compared to sleep as usual in one study. The current study aimed to test an extension of these findings: sleep deprivation under more naturalistic conditions-at home. Polysomnographic recordings show inconsistent sleep deprivation was achieved at home. Fewer intrusive memories were reported on day 1 after the trauma film in the sleep-deprived condition. On day 2 the opposite was found: more intrusive memories in the sleep-deprived condition. However, no significant differences were found with the removal of two participants with extreme values and no difference was found in the total number of intrusive memories reported in the week following the trauma film. Voluntary memory of the trauma film was found to be slightly impaired in the sleep deprivation condition. In conclusion, compared to our eariler findings using total sleep deprivation in a hospital setting, in the current study the use of inconsistent sleep deprivation at home does not replicate the pattern of results on reducing the number of intrusive memories. Considering the conditions under which sleep deprivation (naturalistic versus hospital) was achieved requires further examination.

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  • 24.
    Rukh, Gull
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Dang, Junhua
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Olivo, Gaia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Ciuculete, Diana-Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Schiöth: Funktionell farmakologi. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Personality, lifestyle and job satisfaction: causal association between neuroticism and job satisfaction using Mendelian randomisation in the UK biobank cohort2020Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 10, nr 1, artikel-id 11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Job-related stress has been associated with poor health outcomes but little is known about the causal nature of these findings. We employed Mendelian randomisation (MR) approach to investigate the causal effect of neuroticism, education, and physical activity on job satisfaction. Trait-specific genetic risk score (GRS) based on recent genome wide association studies were used as instrumental variables (IV) using the UK Biobank cohort (N = 315,536). Both single variable and multivariable MR analyses were used to determine the effect of each trait on job satisfaction. We observed a clear evidence of a causal association between neuroticism and job satisfaction. In single variable MR, one standard deviation (1 SD) higher genetically determined neuroticism score (4.07 units) was associated with -0.31 units lower job satisfaction (95% confidence interval (CI): -0.38 to -0.24; P = 9.5 x 10(-20)). The causal associations remained significant after performing sensitivity analyses by excluding invalid genetic variants from GRS(Neuroticism) (beta(95%CI): -0.28(-0.35 to -0.21); P = 3.4 x 10(-15)). Education (0.02; -0.08 to 0.12; 0.67) and physical activity (0.08; -0.34 to 0.50; 0.70) did not show any evidence for causal association with job satisfaction. When genetic instruments for neuroticism, education and physical activity were included together, the association of neuroticism score with job satisfaction was reduced by only -0.01 units, suggesting an independent inverse causal association between neuroticism score (P = 2.7 x 10(-17)) and job satisfaction. Our findings show an independent causal association between neuroticism score and job satisfaction. Physically active lifestyle may help to increase job satisfaction despite presence of high neuroticism scores. Our study highlights the importance of considering the confounding effect of negative personality traits for studies on job satisfaction.

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  • 25.
    Zandian, A.
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Wingard, L.
    Karolinska Inst, Ctr Mol Med, Karolinska Univ Hosp Solna, Dept Clin Neurosci, L8 01, Stockholm, Sweden.;Karolinska Univ Hosp Solna, SLSO, Psykiatri Nordvast, Stockholm, Sweden.;Karolinska Inst, Karolinska Univ Hosp Solna, Ctr Pharmacoepidemiol, Dept Med, Stockholm, Sweden..
    Nilsson, H.
    Karolinska Inst, Ctr Mol Med, Karolinska Univ Hosp Solna, Dept Clin Neurosci, L8 01, Stockholm, Sweden..
    Sjöstedt, Evelina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Johansson, D. X.
    Karolinska Inst, Ctr Mol Med, Karolinska Univ Hosp Solna, Dept Clin Neurosci, L8 01, Stockholm, Sweden..
    Just, D.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Hellstrom, C.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Uhlen, M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Schwenk, J. M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Haemark-Manberg, A.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Norbeck, O.
    Karolinska Inst, Karolinska Univ Hosp Solna, Ctr Mol Med, Dept Med, L8 01, Stockholm, Sweden.;Karolinska Inst, Sect Psychiat, Karolinska Univ Hosp Huddinge, Dept Clin Neurosci,Ctr Psychiat Res, Stockholm, Sweden..
    Owe-Larsson, B.
    Karolinska Inst, Sect Psychiat, Karolinska Univ Hosp Huddinge, Dept Clin Neurosci,Ctr Psychiat Res, Stockholm, Sweden..
    Nilsson, P.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Tomtebodavagen 23A, S-17165 Stockholm, Sweden..
    Persson, M. A. A.
    Karolinska Inst, Ctr Mol Med, Karolinska Univ Hosp Solna, Dept Clin Neurosci, L8 01, Stockholm, Sweden.;Karolinska Univ Hosp Solna, SLSO, Psykiatri Nordvast, Stockholm, Sweden..
    Untargeted screening for novel autoantibodies with prognostic value in first-episode psychosis2017Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, artikel-id e1177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Immunological and inflammatory reactions have been suggested to have a role in the development of schizophrenia, a hypothesis that has recently been supported by genetic data. The aim of our study was to perform an unbiased search for autoantibodies in patients with a first psychotic episode, and to explore the association between any seroreactivity and the development of a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) disorder characterized by chronic or relapsing psychotic symptoms. We collected plasma samples from 53 patients when they were treated for their first-episode psychosis, and 41 non-psychotic controls, after which the patients were followed for a mean duration of 7 years. Thirty patients were diagnosed with schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder or a long-term unspecified nonorganic psychosis during follow-up, whereas 23 patients achieved complete remission. At the end of follow-up, plasma samples were analyzed for IgG reactivity to 2304 fragments of human proteins using a multiplexed affinity proteomic technique. Eight patient samples showed autoreactivity to the N-terminal fragment of the PAGE (P antigen) protein family (PAGE2B/PAGE2/PAGE5), whereas no such autoreactivity was seen among the controls. PAGE autoreactivity was associated with a significantly increased risk of being diagnosed with schizophrenia during follow-up (odds ratio 6.7, relative risk 4.6). An immunohistochemistry analysis using antisera raised against the N-terminal fragment stained an unknown extracellular target in human cortical brain tissue. Our findings suggest that autoreactivity to the N-terminal portion of the PAGE protein family is associated with schizophrenia in a subset of patients with first-episode psychosis.

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  • 26. Ziermans, T
    et al.
    Dumontheil, I
    Roggeman, C
    Peyrard-Janvid, M
    Matsson, H
    Kere, J
    Klingberg, T
    Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.2012Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 2, artikel-id e85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

  • 27.
    Ågren, Thomas
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Furmark, Tomas
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Eriksson, Elias
    Sektionen för farmakologi, Göteborgs universitet.
    Fredrikson, Mats
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Human fear reconsolidation and allelic differences in serotonergic and dopaminergic genes2012Ingår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 2, artikel-id e76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fear memory persistence, central for the development and maintenance of anxiety disorders, is partially genetically controlled. Recently, consolidation and reconsolidation processes have been reported to affect fear memory stability and integrity. This study explored the impact of reconsolidation processes and genetic make-up on fear reacquisition by manipulating reconsolidation using extinction performed outside or inside a reconsolidation interval. Reacquisition measured by skin conductance responses was stronger in individuals that extinguished outside (6 h) than inside (10 min) the reconsolidation interval. However, the effect was predominantly present in val/val homozygotes of the functional val158met polymorphism of the Catechol O-methyltransferase (COMT) enzyme and in short allele carriers of the serotonin transporter length 5-HTTLPR polymorphism. These results demonstrate that reconsolidation of human fear memory is influenced by dopamine and serotonin related genes.

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