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  • 1.
    Artur de la Villarmois, Emilce
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Gabach, Laura A
    Bianconi, Santiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Poretti, Maria Belen
    Occhieppo, Victoria
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Carlini, Valeria P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Pérez, Mariela Fernanda
    Pharmacological NOS-1 Inhibition Within the Hippocampus Prevented Expression of Cocaine Sensitization: Correlation with Reduced Synaptic Transmission.2019In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182Article in journal (Refereed)
    Abstract [en]

    Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15 mg/kg/day i.p.) for 5 days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5 days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.

  • 2.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Characterization of five transmembrane proteins: With focus on the Tweety, Sidoreflexin, and YIP1 domain familiesManuscript (preprint) (Other academic)
    Abstract [en]

    Transmembrane proteins are involved in many essential cell processes such as signal transduction, transport, and protein trafficking, and hence many are implicated in different disease pathways. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e. the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. This analysis investigates the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). More than half of the 58 proteins identified with the 5TM architecture belong to twelve families with two or more members, with ten complete families that do not have any other homologous human proteins identified. Interestingly, more than half the proteins in the dataset function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in large contrast with other TM families. The three major 5TM families include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that act as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport.  About 30% of the 5TM proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM providing details of the unique characteristics

  • 3.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Classification of Trispanins: A Diverse Group of Proteins That Function in Membrane Synthesis and Transport Mechanisms.2019In: Frontiers in cell and developmental biology, ISSN 2296-634X, Vol. 7, article id 386Article in journal (Refereed)
    Abstract [en]

    As the structure and functions of proteins are correlated, investigating groups of proteins with the same gross structure may provide important insights about their functional roles. Trispanins, proteins that contain three alpha-helical transmembrane (3TM) regions, have not been previously studied considering their transmembrane features. Our comprehensive identification and classification using bioinformatic methods describe 152 3TM proteins. These proteins are frequently involved in membrane biosynthesis and lipid biogenesis, protein trafficking, catabolic processes, and in particular signal transduction due to the large ionotropic glutamate receptor family. Proteins that localize to intracellular compartments are overrepresented in the dataset in comparison to the entire human transmembrane proteome, and nearly 45% localize specifically to the endoplasmic reticulum (ER). Furthermore, nearly 20% of the trispanins function in lipid metabolic processes and transport, which are also overrepresented. Nearly one-third of trispanins are identified as being targeted by drugs and/or being associated with diseases. A high number of 3TMs have unknown functions and based on this analysis we speculate on the functional involvement of uncharacterized trispanins in relationship to disease or important cellular activities. This first overall study of trispanins provides a unique analysis of a diverse group of membrane proteins.

  • 4.
    Boström, Adrian E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chatzittofis, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Flanagan, John N
    Krattinger, Regina
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Kullak-Ublick, Gerd A
    Öberg, Katarina Görts
    Arver, Stefan
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jokinen, Jussi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, p. 1-16Article in journal (Refereed)
    Abstract [en]

    Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification 'Compulsive Sexual Behavior Disorder' is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD - cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.

  • 5.
    Ciuculete, Diana M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Voisin, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Kular, Lara
    Welihinda, Nipuni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jagodic, Maja
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression.2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, p. 1-18Article in journal (Refereed)
    Abstract [en]

    Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw<1e-4) and susceptibility for suicidal symptoms (padj.<0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.<0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region.

  • 6.
    Dang, Junhua
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Hagger, Martin S.
    Univ Calif Merced, Dept Psychol Sci, Merced, CA USA;Univ Jyvaskyla, Fac Sport & Hlth Sci, Jyvaskyla, Finland;Univ Calif Merced, Sch Social Sci Humanities & Arts, Psychol Sci, 5200 N Lake Rd, Merced, CA 95343 USA.
    Time to Set a New Research Agenda for Ego Depletion and Self-Control2019In: Social Psychology, ISSN 1864-9335, E-ISSN 2151-2590, Vol. 50, no 5-6, p. 277-281Article in journal (Other academic)
  • 7.
    Dyakova, Olga
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Nordström: Motion Vision.
    Rångtell, Frida H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Nordström, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Nordström: Motion Vision. Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Acute sleep loss induces signs of visual discomfort in young men2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 28, no 6, article id e12837Article in journal (Refereed)
    Abstract [en]

    Acute sleep loss influences visual processes in humans, such as recognizing facial emotions. However, to the best of our knowledge, no study till date has examined whether acute sleep loss alters visual comfort when looking at images. One image statistic that can be used to investigate the level of visual comfort experienced under visual encoding is the slope of the amplitude spectrum, also referred to as the slope constant. The slope constant describes the spatial distribution of pixel intensities and deviations from the natural slope constant can induce visual discomfort. In the present counterbalanced crossover design study, 11 young men with normal or corrected-to-normal vision participated in two experimental conditions: one night of sleep loss and one night of sleep. In the morning after each intervention, subjects performed a computerized psychophysics task. Specifically, they were required to adjust the slope constant of images depicting natural landscapes and close-ups with a randomly chosen initial slope constant until they perceived each image as most natural looking. Subjects also rated the pleasantness of each selected image. Our analysis showed that following sleep loss, higher slope constants were perceived as most natural looking when viewing images of natural landscapes. Images with a higher slope constant are generally perceived as blurrier. The selected images were also rated as less pleasant after sleep loss. No such differences between the experimental conditions were noted for images of close-ups. The results suggest that sleep loss induces signs of visual discomfort in young men. Possible implications of these findings are discussed.

  • 8.
    Fredriksson, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sreedharan, Smitha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nordenankar, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Lindberg, Frida A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hutchinson, Ashley
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Eriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Roshanbin, Sahar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Klockars, Anica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Todkar, Aniruddha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Hägglund, Maria G
    Hellsten, Sofie V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hindlycke, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Västermark, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    K, Cheng
    Kullander, Klas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Moazzami, Ali
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    The polyamine transporter Slc18b1(VPAT) is important for both short and long time memory and for regulation of polyamine content in the brain.2019In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 15, no 12, article id e1008455Article in journal (Refereed)
    Abstract [en]

    SLC18B1 is a sister gene to the vesicular monoamine and acetylcholine transporters, and the only known polyamine transporter, with unknown physiological role. We reveal that Slc18b1 knock out mice has significantly reduced polyamine content in the brain providing the first evidence that Slc18b1 is functionally required for regulating polyamine levels. We found that this mouse has impaired short and long term memory in novel object recognition, radial arm maze and self-administration paradigms. We also show that Slc18b1 KO mice have altered expression of genes involved in Long Term Potentiation, plasticity, calcium signalling and synaptic functions and that expression of components of GABA and glutamate signalling are changed. We further observe a partial resistance to diazepam, manifested as significantly lowered reduction in locomotion after diazepam treatment. We suggest that removal of Slc18b1 leads to reduction of polyamine contents in neurons, resulting in reduced GABA signalling due to long-term reduction in glutamatergic signalling.

  • 9.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Campus Biomed Roma, Area Diagnost Imaging, Ctr Integrated Res, Rome, Italy.
    Carducci, Filippo
    Sapienza Univ, Neuroimaging Lab, Dept Physiol & Pharmacol, Rome, Italy.
    Piervincenzi, Claudia
    Sapienza Univ, Neuroimaging Lab, Dept Physiol & Pharmacol, Rome, Italy.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Altered thalamo-cortical and occipital-parietal-temporal-frontal white matter connections in patients with anorexia and bulimia nervosa: a systematic review of diffusion tensor imaging studies2019In: Journal of Psychiatry & Neuroscience, ISSN 1180-4882, E-ISSN 1488-2434, Vol. 44, no 5, p. 324-339Article, review/survey (Refereed)
    Abstract [en]

    Background: Anorexia nervosa and bulimia nervosa are complex mental disorders, and their etiology is still not fully understood. This paper reviews the literature on diffusion tensor imaging studies in patients with anorexia nervosa and bulimia nervosa to explore the usefulness of white matter microstructural analysis in understanding the pathophysiology of eating disorders.

    Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify diffusion tensor imaging studies that compared patients with an eating disorder to control groups. We searched relevant databases for studies published from database inception to August 2018, using combinations of select keywords. We categorized white matter tracts according to their 3 main classes: projection (i.e., thalamo-cortical), association (i.e., occipital-parietal-temporal-frontal) and commissural (e.g., corpus callosum).

    Results: We included 19 papers that investigated a total of 427 participants with current or previous eating disorders and 444 controls. Overall, the studies used different diffusion tensor imaging approaches and showed widespread white matter abnormalities in patients with eating disorders. Despite differences among the studies, patients with anorexia nervosa showed mainly white matter microstructural abnormalities of thalamo-cortical tracts (i.e., corona radiata, thalamic radiations) and occipital-parietal-temporal-frontal tracts (i.e., left superior longitudinal and inferior fronto-occipital fasciculi). It was less clear whether white matter alterations persist after recovery from anorexia nervosa. Available data on bulimia nervosa were partially similar to those for anorexia nervosa.

    Limitations: Study sample composition and diffusion tensor imaging analysis techniques were heterogeneous. The number of studies on bulimia nervosa was too limited to be conclusive.

    Conclusion: White matter microstructure appears to be affected in anorexia nervosa, and these alterations may play a role in the pathophysiology of this eating disorder. Although we found white matter alterations in bulimia nervosa that were similar to those in anorexia nervosa, white matter changes in bulimia nervosa remain poorly investigated, and these findings were less conclusive. Further studies with longitudinal designs and multi-approach analyses are needed to better understand the role of white matter changes in eating disorders.

  • 10.
    Herrera, Guadalupe
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Nacl Cordoba, Fac Ciencias Quim, Dept Farmacol, IFEC CONICET, Haya de la Torre & Medina Allende Ciudad Univ, RA-5000 Cordoba, Argentina.
    Calfa, Gaston
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Nacl Cordoba, Fac Ciencias Quim, Dept Farmacol, IFEC CONICET, Haya de la Torre & Medina Allende Ciudad Univ, RA-5000 Cordoba, Argentina.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Lasaga, Mercedes
    Inst Invest Biomed INBIOMED UBA CONICET, Fac Med, Buenos Aires, DF, Argentina.
    Scimonelli, Teresa
    Univ Nacl Cordoba, Fac Ciencias Quim, Dept Farmacol, IFEC CONICET, Haya de la Torre & Medina Allende Ciudad Univ, RA-5000 Cordoba, Argentina.
    Memory consolidation impairment induced by Interleukin-1 beta is associated with changes in hippocampal structural plasticity2019In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 370, article id 111969Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory cytokines, particularly Interleukin-1 beta (IL-1 beta), can affect cognitive processes such as learning and memory. The aim of this study was to establish whether the effect of IL-1 beta on contextual fear memory is associated with changes in hippocampal structural plasticity. We also studied the effect of alpha-melanocyte-stimulating hormone (alpha-MSH), a potent anti-inflammatory and neuro-protective peptide. Different groups of animals were implanted bilaterally in dorsal hippocampus (DH). After recovery they were conditioned for contextual fear memory and received the different treatments (vehicle, IL-1 beta, alpha-MSH or IL-1 beta + alpha-MSH). Memory was assessed 24 hs after conditioning and immediately after rats were perfused for dendritic spine analysis. Our results show that local hippocampal administration of IL-1 beta just after memory encoding induced impairment in contextual memory and a reduction in the total density of CA1 hippocampal dendritic spines, particularly the mature ones. alpha-MSH administration reversed the IL-1 beta induced changes. The results suggest that neuro-inflammation induced by IL-1 beta interferes with experience-dependent structural plasticity in DH whereas alpha-MSH has a beneficial modulatory role in preventing this effect.

  • 11.
    Kanders, Sofia H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Pisanu, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Castelao, Enrique
    Pistis, Giorgio
    Gholam-Rezaee, Mehdi
    Eap, Chin B.
    Preisig, Martin
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants2019In: Drug development research (Print), ISSN 0272-4391, E-ISSN 1098-2299, p. 1-12Article in journal (Refereed)
    Abstract [en]

    The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population-based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES-D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES-D score, occurrence of a major depressive episode (MDE) during follow-up and regular antidepressant treatment during the 6 months preceding follow-up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES-D score (p = .001). The HTR1A rs878567 variant was associated with ln CES-D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19) CC homozygotes showed a six-fold higher likelihood of regular AD therapy at follow-up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.

  • 12.
    Moulin, Thiago C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Petiz, Lyvia L.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Rayêe, Danielle
    Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Winne, Jessica
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Maia, Roberto G.
    Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Lima da Cruz, Rafael V.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Amaral, Olavo B.
    Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazi.
    Leão, Richardson N.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus2019In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 29, no 8, p. 755-761Article in journal (Refereed)
    Abstract [en]

    Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

  • 13.
    Moulin, Thiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    A possible role for pollutants in mental disorders via gut microbiota2019In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 693, article id 133639Article in journal (Other academic)
  • 14.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Brain Structure and Function in Adolescents with Atypical Anorexia Nervosa2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atypical anorexia nervosa (AAN) has a high incidence in adolescents, resulting in significant morbidity and mortality. The weight loss is generally less pronounced than that experienced in full-syndrome anorexia nervosa (AN), but the medical consequences can be as severe. Neuroimaging could improve our knowledge regarding the pathogenesis of eating disorders, however research on adolescents is limited, and no neuroimaging studies have been conducted in AAN. In paper I, we investigated brain structure through a voxel-based morphometry analysis in 22 drug-naïve adolescent females newly-diagnosed with AAN, and 38 age- and sex-matched healthy controls. In Paper II, we investigated white matter microstructural integrity on 25 drug-naïve adolescent patients with AAN and 25 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. No differences in brain structure could be detected, indicating preserved regional grey matter volumes and white matter diffusivity in patients with AAN compared to controls. These findings suggest that previous observations of brain structure alterations in full syndrome AN may constitute state-related consequences of severe underweight. Alternatively, the preservation of brain structure might indeed differentiate AAN from AN. In paper III, we investigated resting-state functional connectivity in 22 drug-naïve adolescent patients with AAN, and 24 healthy controls. We report reduced connectivity in patients in brain areas involved in face-processing and social cognition, while an increased connectivity, correlating with depressive symptoms, was found in areas involved in the multimodal integration of sensory stimuli, aesthetic judgment, and social rejection anxiety. These findings point toward a core role for an altered development of socio-emotional skills in the pathogenesis of AAN. In Paper IV, we investigated neural connectivity underlying visual processing of foods with different caloric content in a sample of 28 adolescent females diagnosed with AAN, and 33 age- and sex-matched healthy controls. Our results showed higher connectivity in patients in pathways related to the integration of sensory input and memory retrieval, in response to food with high caloric content. This, however, was coupled to lower connectivity in salience and attentional networks, and lower connectivity between areas involved in visual food cues processing and appetite regulatory regions. Thus, despite food with high caloric content is associated to greater processing of somatosensory information in patients, it is attributed less salience and engages patients’ attention less than food with low caloric content.

    List of papers
    1. Atypical anorexia nervosa is not related to brain structural changes in newly diagnosed adolescent patients.
    Open this publication in new window or tab >>Atypical anorexia nervosa is not related to brain structural changes in newly diagnosed adolescent patients.
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    2018 (English)In: International Journal of Eating Disorders, ISSN 0276-3478, E-ISSN 1098-108X, Vol. 51, no 1, p. 39-45Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE: Patients with atypical anorexia nervosa (AN) have many features overlapping with AN in terms of genetic risk, age of onset, psychopathology and prognosis of outcome, although the weight loss may not be a core factor. While brain structural alterations have been reported in AN, there are currently no data regarding atypical AN patients.

    METHOD: We investigated brain structure through a voxel-based morphometry analysis in 22 adolescent females newly-diagnosed with atypical AN, and 38 age- and sex-matched healthy controls (HC). ED-related psychopathology, impulsiveness and obsessive-compulsive traits were assessed with the Eating Disorder Examination Questionnaire (EDE-Q), Barratt Impulsiveness Scale (BIS-11) and Obsessive-compulsive Inventory Revised (OCI-R), respectively. Body mass index (BMI) was also calculated.

    RESULTS: Patients and HC differed significantly on BMI (p < .002), EDE-Q total score (p < .000) and OCI-R total score (p < .000). No differences could be detected in grey matter (GM) regional volume between groups.

    DISCUSSION: The ED-related cognitions in atypical AN patients would suggest that atypical AN and AN could be part of the same spectrum of restrictive-ED. However, contrary to previous reports in AN, our atypical AN patients did not show any GM volume reduction. The different degree of weight loss might play a role in determining such discrepancy. Alternatively, the preservation of GM volume might indeed differentiate atypical AN from AN.

    Keywords
    MRI, OSFED, VBM, adolescent, anorexia, eating disorders, imaging
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-336179 (URN)10.1002/eat.22805 (DOI)000418270800005 ()29215777 (PubMedID)
    Funder
    Swedish Research Council FormasSwedish Research CouncilThe Swedish Brain Foundation
    Available from: 2017-12-12 Created: 2017-12-12 Last updated: 2019-07-30Bibliographically approved
    2. Preserved white matter microstructure in adolescent patients with atypical anorexia nervosa
    Open this publication in new window or tab >>Preserved white matter microstructure in adolescent patients with atypical anorexia nervosa
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    2019 (English)In: International Journal of Eating Disorders, ISSN 0276-3478, E-ISSN 1098-108X, Vol. 52, no 2, p. 166-174Article in journal (Refereed) Published
    Abstract [en]

    Objective: Patients with atypical anorexia nervosa (AN) are often in the normal-weight range at presentation; however, signs of starvation and medical instability are not rare. White matter (WM) microstructural correlates of atypical AN have not yet been investigated, leaving an important gap in our knowledge regarding the neural pathogenesis of this disorder.

    Method: We investigated WM microstructural integrity in 25 drug-naive adolescent patients with atypical AN and 25 healthy controls, using diffusion tensor imaging (DTI) with a tract-based spatial statistics (TBSS) approach. Psychological variables related to the eating disorder and depressive symptoms were also evaluated by administering the eating disorder examination questionnaire (EDE-Q) and the Montgomery-angstrom sberg depression rating scale (MADRS-S) respectively, to all participants.

    Results: Patients and controls were in the normal-weight range and did not differ from the body mass index standard deviations for their age. No between groups difference in WM microstructure could be detected.

    Discussion: Our findings support the hypothesis that brain structural alterations may not be associated to early-stage atypical AN. These findings also suggest that previous observations of alterations in WM microstructure in full syndrome AN may constitute state-related consequences of severe weight loss. Whether the preservation of WM structure is a pathogenetically discriminant feature of atypical AN or only an effect of a less severe nutritional disturbance, will have to be verified by future studies on larger samples, possibly directly comparing AN and atypical AN.

    Keywords
    adolescent, anorexia nervosa, brain, cognitive neuroscience, diffusion tensor imaging, feeding and eating disorders, neuroimaging
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-378685 (URN)10.1002/eat.23012 (DOI)000458301700008 ()30676658 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain Foundation
    Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2020-01-09Bibliographically approved
    3. Reduced resting-state connectivity in areas involved in processing of face-related social cues in female adolescents with atypical anorexia nervosa
    Open this publication in new window or tab >>Reduced resting-state connectivity in areas involved in processing of face-related social cues in female adolescents with atypical anorexia nervosa
    Show others...
    2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 275Article in journal (Refereed) Published
    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.

    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-373370 (URN)10.1038/s41398-018-0333-1 (DOI)000454240100002 ()30546060 (PubMedID)
    Funder
    Swedish Research Council FormasSwedish Research CouncilThe Swedish Brain Foundation
    Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-07-30Bibliographically approved
    4. Functional connectivity underlying hedonic response to food in female adolescents with atypical AN: The role of somatosensory and salience networks
    Open this publication in new window or tab >>Functional connectivity underlying hedonic response to food in female adolescents with atypical AN: The role of somatosensory and salience networks
    Show others...
    2019 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, article id 276Article in journal (Refereed) Published
    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.

    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:uu:diva-385193 (URN)10.1038/s41398-019-0617-0 (DOI)000497957200002 ()31699967 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain FoundationThe Kempe FoundationsTore Nilsons Stiftelse för medicinsk forskningGunvor och Josef Anérs stiftelseSwedish Research Council Formas
    Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2020-01-09Bibliographically approved
  • 15.
    Olivo, Gaia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala Univ, Dept Neurosci Funct Pharmacol, S-75124 Uppsala, Sweden.
    Gaudio, Santino
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Campus Biomed Roma, CIR, Area Diagnost Imaging, I-00128 Rome, Italy.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119146, Russia.
    Brain and Cognitive Development in Adolescents with Anorexia Nervosa: A Systematic Review of fMRI Studies2019In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 8, article id 1907Article, review/survey (Refereed)
    Abstract [en]

    Anorexia nervosa (AN) is an eating disorder often occurring in adolescence. AN has one of the highest mortality rates amongst psychiatric illnesses and is associated with medical complications and high risk for psychiatric comorbidities, persisting after treatment. Remission rates range from 23% to 33%. Moreover, weight recovery does not necessarily reflect cognitive recovery. This issue is of particular interest in adolescence, characterized by progressive changes in brain structure and functional circuitries, and fast cognitive development. We reviewed existing literature on fMRI studies in adolescents diagnosed with AN, following PRISMA guidelines. Eligible studies had to: (1) be written in English; (2) include only adolescent participants; and (3) use block-design fMRI. We propose a pathogenic model based on normal and AN-related neural and cognitive maturation during adolescence. We propose that underweight and delayed puberty-caused by genetic, environmental, and neurobehavioral factors-can affect brain and cognitive development and lead to impaired cognitive flexibility, which in turn sustains the perpetuation of aberrant behaviors in a vicious cycle. Moreover, greater punishment sensitivity causes a shift toward punishment-based learning, leading to greater anxiety and ultimately to excessive reappraisal over emotions. Treatments combining physiological and neurobehavioral rationales must be adopted to improve outcomes and prevent relapses.

  • 16.
    Olivo, Gaia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Zhukovsky, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Salonen-Ros, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. 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 networks2019In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, article id 276Article in journal (Refereed)
    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.

  • 17.
    Paula Cornejo, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Castrogiovanni, Daniel
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Reynaldo, Mirta
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Marie, Jacky
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247,CNRS,ENSCM, Montpellier, France.
    Fehrentz, Jean-Alain
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247,CNRS,ENSCM, Montpellier, France.
    Perello, Mario
    Natl Univ La Plata, Lab Neurophysiol, Multidisciplinary Inst Cell Biol IMBICE, Argentine Res Council CONICET, La Plata, Buenos Aires, Argentina;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina.
    Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model2019In: Journal of neuroendocrinology (Print), ISSN 0953-8194, E-ISSN 1365-2826, Vol. 31, no 10, article id e12785Article in journal (Refereed)
    Abstract [en]

    The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver-expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin-evoked activity. GHSR also displays ligand-independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake-related behaviours, including binge eating. Previously, we reported that GHSR-deficient mice daily and time-limited exposed to a high-fat (HF) diet display an attenuated binge-like HF intake compared to wild-type mice. In the present study, we aimed to determine whether ligand-independent GHSR activity affects binge-like HF intake in a 4-day binge-like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge-like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K-(D-1-Nal)-FwLL-NH2, which are both blockers of constitutive GHSR activity, reduced binge-like HF intake, whereas central administration of ghrelin or the ghrelin-evoked GHSR activity blockers [D-Lys3]-GHRP-6 and JMV2959 did not modify binge-like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge-like HF intake in mice independently of plasma levels of ghrelin and LEAP2.

  • 18.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Lundin, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Preisig, Martin
    Gholam-Rezaee, Mehdi
    Castelao, Enrique
    Pistis, Giorgio
    Merikangas, Kathleen R
    Glaus, Jennifer
    Squassina, Alessio
    Del Zompo, Maria
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Major depression subtypes are differentially associated with migraine subtype, prevalence and severity.2019In: Cephalalgia, ISSN 0333-1024, E-ISSN 1468-2982, article id 333102419884935Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Migraine and major depressive disorder show a high rate of comorbidity, but little is known about the associations between the subtypes of major depressive disorder and migraine. In this cross-sectional study we aimed at investigating a) the lifetime associations between the atypical, melancholic, combined and unspecified subtype of major depressive disorder and migraine with and without aura and b) the associations between major depressive disorder and its subtypes and the severity of migraine.

    METHODS: A total of 446 subjects with migraine (migraine without aura: n = 294; migraine with aura: n = 152) and 2511 controls from the population-based CoLaus/PsyCoLaus study, Switzerland, were included. Associations between major depressive disorder subtypes and migraine characteristics were tested using binary logistic or linear regression.

    RESULTS: Melancholic, combined and unspecified major depressive disorder were associated with increased frequency of migraine with aura, whereas only melancholic major depressive disorder was associated with increased frequency of migraine without aura. Lifetime and unspecified major depressive disorder were associated with severe migraine intensity among subjects with migraine with aura but not migraine without aura, while combined major depressive disorder was associated with higher migraine frequency independently from migraine subtype.

    CONCLUSION: This study suggests that melancholic but not atypical major depressive disorder is associated with migraine and migraine subtypes. Future studies exploring pathophysiological mechanisms shared between melancholic depression and migraine are warranted.

  • 19.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy.
    Squassina, Alessio
    Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Treatment-Resistant Schizophrenia: Insights From Genetic Studies and Machine Learning Approaches2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 617Article, review/survey (Refereed)
    Abstract [en]

    Schizophrenia (SCZ) is a severe psychiatric disorder affecting approximately 23 million people worldwide. It is considered the eighth leading cause of disability according to the Wood Health Organization and is associated with a significant reduction in life expectancy. Antipsychotics represent the first-choice treatment in SCZ, but approximately 30% of patients fail to respond to acute treatment. These patients are generally defined as treatment-resistant and are eligible for clozapine treatment. Treatment-resistant patients show a more severe course of the disease, but it has been suggested that treatment-resistant schizophrenia (TRS) may constitute a distinct phenotype that is more than just a more severe form of SCZ. TRS is heritable, and genetics has been shown to play an important role in modulating response to antipsychotics. Important efforts have been put into place in order to better understand the genetic architecture of TRS, with the main goal of identifying reliable predictive markers that might improve the management and quality of life of TRS patients. However, the number of candidate gene and genome-wide association studies specifically focused on TRS is limited, and to date, findings do not allow the disentanglement of its polygenic nature. More recent studies implemented polygenic risk score, gene-based and machine learning methods to explore the genetics of TRS, reporting promising findings. In this review, we present an overview on the genetics of TRS, particularly focusing our discussion on studies implementing polygenic approaches.

  • 20.
    Pisanu, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. 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 BMI2019In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 9, article id 315Article in journal (Refereed)
    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.

  • 21.
    Rukh, Gull
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Dang, Junhua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. 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 cohort2020In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 10, no 1, article id 11Article in journal (Refereed)
    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.

  • 22.
    Squassina, Alessio
    et al.
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy;Dalhousie Univ, Dept Psychiat, Halifax, NS, Canada.
    Meloni, Anna
    Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Chillotti, Caterina
    Univ Hosp Cagliari, Unit Clin Pharmacol, Cagliari, Italy.
    Pisanu, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy.
    Zinc finger proteins in psychiatric disorders and response to psychotropic medications2019In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 29, no 5, p. 132-141Article, review/survey (Refereed)
    Abstract [en]

    Zinc finger proteins are a large family of abundantly expressed small motifs that play a crucial role in a wide range of physiological and pathophysiological mechanisms. Findings published so far support an involvement of zinc fingers in psychiatric disorders. Most of the evidence has been provided for the zinc finger protein 804A (ZNF804A) gene, which has been suggested to be implicated in schizophrenia and bipolar disorder. This evidence has been corroborated by a wide range of functional studies showing that ZNF804A regulates the expression of genes involved in cell adhesion and plays a crucial role in neurite formation and maintenance of dendritic spines. On the other hand, far less is known on other zinc finger proteins and their involvement in psychiatric disorders. In this review, we discussed studies exploring the role of zinc finger proteins in schizophrenia, bipolar disorder, and major depressive disorder as well as in pharmacogenetics of psychotropic drugs.

  • 23.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Associations between chronotype, MTNR1B genotype and risk of type 2 diabetes in UK Biobank2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796Article in journal (Refereed)
    Abstract [en]

    Objective

    To examine the association between the MTNR1B G risk allele, type 2 diabetes (T2D) and chronotype in the UK Biobank.

    Methods

    Data from the baseline investigation of the UK Biobank were utilized (n = 337 083 White British; mean age: 56.9 years; 54% women). MTNR1B rs10830963 was directly genotyped [CC (reference group), CG and GG]. Chronotype was divided into four categories: definitely morning (reference group); more morning than evening; more evening than morning; and definitely evening. Logistic regression analyses were performed to estimate odds ratios and 95% confidence intervals (CIs) for T2D, controlling for age, sex and other confounders.

    Results

    Carriers of the rs10830963 risk allele had a higher risk of T2D [CG vs. CC: OR (95% CI) 1.10 (1.07, 1.15); GG vs. CC: 1.21 (1.14, 1.29)]. Compared with definitely morning chronotype, participants with definitely evening chronotype exhibited the highest risk of T2D [1.25 (1.17, 1.33)]. Despite a nonsignificant interaction between chronotype and the risk allele [0.98 (0.94, 1.01), P = 0.176 for interaction term], we found that definitely evening chronotype (vs. definitely morning) was linked with a higher risk of T2D amongst CC and CG but not GG carriers. Additionally, we saw that the GG genotype (vs. CC) was associated with a higher risk of T2D across all chronotype categories, except for definitely evening.

    Conclusion

    Our findings suggest that the MTNR1B G risk allele and late chronotype increase the risk of T2D. The association between late chronotype and higher risk of T2D appears to vary across MTNR1B rs10830963 genotypes.

  • 24.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cook, Jesse D.
    Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53706 USA.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Consumer sleep trackers: a new tool to fight the hidden epidemic of obstructive sleep apnoea?2019In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 7, no 12, p. 1012-1012Article in journal (Other academic)
  • 25.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    Univ Helsinki, Dept Neurol Sci, Helsinki, Finland;Helsinki Sleep Clin, VitalMed Res Ctr, Helsinki, Finland.
    Lange, Tanja
    Univ Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, Germany.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients2019In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 59, p. 42-50Article, review/survey (Refereed)
    Abstract [en]

    Sleep and circadian disruptions are frequently observed in patients across hospital wards. This is alarming, since impaired nocturnal sleep and disruption of a normal circadian rhythm can compromise health and disturb processes involved in recovery from illness (eg, immune functions). With this in mind, the present narrative review discusses how patient characteristics (sleep disorders, anxiety, stress, chronotype, and disease), hospital routines (pain management, timing of medication, nocturnal vital sign monitoring, and physical inactivity), and hospital environment (light and noise) may all contribute to sleep disturbances and circadian misalignment in patients. We also propose hospital-based strategies that may help reduce sleep and circadian disruptions in patients admitted to the hospital. (C) 2018 The Authors. Published by Elsevier B.V.

  • 26.
    Tan, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    Univ Helsinki, Dept Neurol Sci, Helsinki, Finland.
    Lange, Tanja
    Helsinki Sleep Clin, VitalMed Res Ctr, Helsinki, Finland.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Response to comment on "A narrative review of interventions for improving sleep and reducing circadian disruption in medical inpatients"2019In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 59, p. 53-53Article in journal (Other academic)
  • 27.
    Titova, Olga E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Elmståhl, Sölve
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults.2020In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 111, article id 104472Article in journal (Refereed)
    Abstract [en]

    Executive function is defined as a set of cognitive skills that are necessary to plan, monitor, and execute a sequence of goal-directed complex actions. Executive function is influenced by a variety of factors, including habitual sleep duration and diabetes. In the present study, we investigated in 18,769 Swedish adults (mean age: 61 y) the association between executive function, diabetes, and self-reported sleep duration. We observed a significant interaction between diabetes and sleep duration for the Trail Making Test (TMT) ratio (P < 0.01). This ratio is a measure of executive function where higher values indicate worse performance. Among diabetic participants (n = 1,523), long (defined as ≥9 h per day) vs. normal sleep duration (defined as 7-8 hours per day) was associated with a higher TMT ratio (P < 0.05). Similar significant results were observed in diabetic individuals without pharmacological treatment for diabetes (n = 1,062). Among non-diabetic participants (n = 17,246), no association between long sleep duration and the TMT ratio was observed (P > 0.05). Instead, short (defined as <7 h per day) vs. normal sleep duration was linked to a higher TMT ratio (P < 0.05). These findings suggest that the association between sleep duration and executive function differs between diabetic and non-diabetic middle-aged and older adults. Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

  • 28.
    van Egmond, Lieve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ekman, Martin
    Summer Inst Hist Geophys, Haraldsby, Aland Islands, Sweden.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Bed and rise times during the Age of Enlightenment: A case report2019In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 28, no 6, article id e12862Article in journal (Refereed)
    Abstract [en]

    Studies have shown that our modern electrical lighting environment reduces naturally occurring seasonal variations in sleep-wake rhythms, such as longer sleep during the winter versus summer. However, less is known about how timing and duration of sleep were affected by the seasons in the premodern era, before the invention of electrical lighting. The Swedish researcher Olof Hiorter collected and documented geophysical data every hour during wakefulness in Uppsala, Sweden, between December 1746 and November 1747. In this way, his bed and rise times could be approximated. The data revealed that Hiorter's rise times occurred around 1 hr before sunrise in winter versus 1 hr after sunrise in summer. No such association was observed between the time of sunset and Hiorter's bedtimes. Finally, the time in bed was about 3.5-4 hr shorter in summer compared to winter. This 273-year-old case report suggests that time in bed and rise times of people from the premodern era exhibited seasonal variations.

  • 29.
    van Egmond, Lieve
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sjögren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Association between Healthy Dietary Patterns and Self-Reported Sleep Disturbances in Older Men: The ULSAM Study2019In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 5, article id 1029Article in journal (Refereed)
    Abstract [en]

    To date, little is known about how dietary patterns may link to measures of sleep quality in older subjects, who often suffer from sleep problems. Here, we investigated, in an older male population from Sweden (n = 970; aged 71 +/- 1 year), whether adherence to the Healthy Diet Indicator (HDI; based on recommendations from the World Health Organization) or the Mediterranean Diet (MD) is linked to sleep disturbances. The diet scores were calculated using a seven-day food diary, and self-reported sleep initiation or maintenance problems were assessed by questionnaires. When adjusted for potential confounders, no associations between dietary scores and sleep parameters were found. In contrast, low consumption of milk and dairy products one of the dietary features of the MD was associated with better subjective sleep initiation. This association was, however, not found in men with adequate reports of daily energy intake (similar to 54% of the cohort). To summarize, our findings do not suggest that older men can mitigate perceived difficulties to fall and stay asleep by adhering to either the HDI or MD. Whether low consumption of milk and dairy products can facilitate sleep initiation must be confirmed in future studies by utilizing objective measures of sleep such as polysomnography. Finally, when investigating associations between dietary patterns and sleep, particular attention should be paid to the potential confounder of inadequate reporting of energy intake.

  • 30.
    Wang, Ludi
    et al.
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chang, Qing
    Shanghai Univ Med & Hlth Sci, Jiading Dist Cent Hosp, Shanghai Gen Practice Med Educ & Res Ctr, Shanghai 201800, Peoples R China.
    Chen, Jiangen
    Jiading Ind Dist Community Hlth Serv Ctr, Dept Gen Med, Shanghai 201800, Peoples R China.
    Zhou, Xiaoguang
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China;Minjiang Univ, Sch Econ & Management, Fuzhou 350108, Fujian, Peoples R China.
    Deep Ensemble Detection of Congestive Heart Failure Using Short-Term RR Intervals2019In: IEEE Access, E-ISSN 2169-3536, Vol. 7, p. 69559-69574Article in journal (Refereed)
    Abstract [en]

    Heart rate variability (HRV) is an effective predictor of congestive heart failure (CHF). However, important challenges exist regarding the effective temporal feature extraction and efficient classification using high-dimensional HRV representations. To solve these challenges, an ensemble method for CHF detection using short-term HRV data and deep neural networks was proposed. In this paper, five opensource databases, the BIDMC CHF database (BIDMC-CHF), CHF RR interval database (CHF-RR), MITBIH normal sinus rhythm (NSR) database, fantasia database (ED), and NSR RR interval database (NSR-RR), were used. Additionally, three RR segment length types (N = 500, 1000, and 2000) were used to evaluate the proposed method. First, we extracted the expert features of RR intervals (RRIs) and then built a long short-term memory-convolutional neural network-based network to extract deep-learning (DL) features automatically. Finally, an ensemble classifier was used for CHF detection using the above features. With blindfold validation (three CHF subjects and three normal subjects), the proposed method achieved 99.85%, 99.41%, and 99.17% accuracy on N = 500, 1000, and 2000 length RRIs, respectively, using the BIDMC-CHF, NSR, and FD databases. With blindfold validation (six CHF subjects and six normal subjects), the proposed method achieved 83.84%, 87.54%, and 85.71% accuracy on N = 500, 1000, and 2000 length RRIs, respectively, using the NSR-RR and CHF-RR ndatabases. Based on feature ranking, the significant effectiveness provided by the DL features has been proven. The results have shown that the deep ensemble method can achieve reliable CHF detection using short-term heart rate signals and enable CHF detection through intelligent hardware.

  • 31.
    Wang, Lu-di
    et al.
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Zhou, Wei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Xing, Ying
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    Liu, Na
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Movahedipour, Mahmood
    Beijing Univ Posts & Telecommun, Sch Econ & Management, Beijing 100876, Peoples R China;ACECR, Tehran 141554364, Iran.
    Zhou, Xiao-guang
    Beijing Univ Posts & Telecommun, Automat Sch, Beijing 100876, Peoples R China.
    A novel method based on convolutional neural networks for deriving standard 12-lead ECG from serial 3-lead ECG2019In: FRONTIERS OF INFORMATION TECHNOLOGY & ELECTRONIC ENGINEERING, ISSN 2095-9184, Vol. 20, no 3, p. 405-413Article in journal (Refereed)
    Abstract [en]

    Reconstruction of a 12-lead electrocardiogram (ECG) from a serial 3-lead ECG has been researched in the past to satisfy the need for more wearing comfort and ambulatory situations. The accuracy and real-time performance of traditional methods need to be improved. In this study, we present a novel method based on convolutional neural networks (CNNs) for the synthesis of missing precordial leads. The results show that the proposed method receives better similarity and consumes less time using the PTB database. Particularly, the presented method shows outstanding performance in reconstructing the pathological ECG signal, which is crucial for cardiac diagnosis. Our CNN-based method is shown to be more accurate and time-saving for deployment in non-hospital situations to synthesize a standard 12-lead ECG from a reduced lead-set ECG recording. This is promising for real cardiac care.

  • 32. Weber, Jonasz Jeremiasz
    et al.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Nguyen, Huu Phuc
    Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate2019In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 168, p. 305-318Article, review/survey (Refereed)
    Abstract [en]

    Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to olesoxime's action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.

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