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Gaudio, S., Olivo, G., Zobel, B. B. & Schiöth, H. B. (2018). Altered cerebellar-insular-parietal-cingular subnetwork in adolescents in the earliest stages of anorexia nervosa: a network-based statistic analysis. Translational Psychiatry, 8, Article ID 127.
Open this publication in new window or tab >>Altered cerebellar-insular-parietal-cingular subnetwork in adolescents in the earliest stages of anorexia nervosa: a network-based statistic analysis
2018 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 8, article id 127Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging Psychiatry
Identifiers
urn:nbn:se:uu:diva-361277 (URN)10.1038/s41398-018-0173-z (DOI)000438104500001 ()29980676 (PubMedID)
Available from: 2018-09-27 Created: 2018-09-27 Last updated: 2018-09-27Bibliographically approved
Titova, O. E., Lindberg, E., Elmstahl, S., Lind, L., Schiöth, H. B. & Benedict, C. (2018). Associations Between the Prevalence of Metabolic Syndrome and Sleep Parameters Vary by Age. Frontiers in Endocrinology, 9, Article ID 234.
Open this publication in new window or tab >>Associations Between the Prevalence of Metabolic Syndrome and Sleep Parameters Vary by Age
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2018 (English)In: Frontiers in Endocrinology, ISSN 1664-2392, E-ISSN 1664-2392, Vol. 9, article id 234Article in journal (Refereed) Published
Abstract [en]

Objective: To examine whether the relationship between the metabolic syndrome (MetS) and various sleep parameters [sleep duration, symptoms of sleep-disordered breathing (SDB), and sleep disturbances] varies by age. Methods: Waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol, and fasting glucose were used to determine MetS status in a cohort (N = 19,691) of middle-aged (aged 45-64 years) and older (aged >= 65 years) subjects. Habitual sleep duration (short, <= 6 h/day; normal, 7-8 h/day; and long >= 9 h/day), sleep disturbances (such as problems with falling and staying asleep), and symptoms of sleep-disordered breathing (SDB, such as snoring and sleep apneas) were measured by questionnaires. Results: Among the participants, 4,941 subjects (25.1%) fulfilled the criteria for MetS. In the entire sample, both short and long sleep durations were associated with higher prevalence of MetS as compared to normal sleep duration. When stratified by age, a similar pattern was observed for middle-aged subjects (<65 years old; prevalence ratio (PR) [95% CI], 1.13 [1.06-1.22] for short sleep and 1.26 [1.06-1.50] for long sleep duration). In contrast, in older individuals (>= 65 years old), only long sleep duration was linked to a higher prevalence of MetS (1.26 [1.12-1.42]; P < 0.01 for sleep duration x age). In the entire cohort, having at least one SDB symptom >= 4 times per week was linked to an increased prevalence of MetS; however, the PR was higher in middle-aged subjects compared with older subjects (1.50 [1.38-1.63] vs. 1.36 [1.26-1.47], respectively; P < 0.001 for SDB x age). Finally, independent of subjects' age, reports of sleep disturbances (i.e., at least one symptom >= 4 times per week) were associated with a higher likelihood of having MetS (1.12 [1.06-1.18]; P > 0.05 for sleep disturbance x age). Conclusion: Our results suggest that age may modify the associations between some sleep parameters and the prevalence of MetS.

Keywords
sleep duration, sleep disturbance, sleep-disordered breathing, metabolic syndrome, age
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-356873 (URN)10.3389/fendo.2018.00234 (DOI)000431867800001 ()29867766 (PubMedID)
Funder
Swedish Research Council, 2015-03100The Swedish Brain FoundationNovo Nordisk, NNF14OC0009349
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved
Olivo, G., Solstrand Dahlberg, L., Wiemerslage, L., Swenne, I., Zhukovsky, C., Salonen-Ros, H., . . . Schiöth, H. B. (2018). Atypical anorexia nervosa is not related to brain structural changes in newly diagnosed adolescent patients.. International Journal of Eating Disorders, 51(1), 39-45
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: 2018-02-19Bibliographically approved
Ciuculete, D.-M., Boström, A. E., Tuunainen, A.-K., Sohrabi, F., Kular, L., Jagodic, M., . . . Schiöth, H. B. (2018). Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents. Journal of Psychiatric Research, 102, 44-51
Open this publication in new window or tab >>Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents
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2018 (English)In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 102, p. 44-51Article in journal (Refereed) Published
Abstract [en]

Generalized anxiety disorder (GAD) is highly prevalent among adolescents. An early detection of individuals at risk may prevent later psychiatric condition. Genome-wide studies investigating single nucleotide polymorphisms (SNPs) concluded that a focus on epigenetic mechanisms, which mediate the impact of environmental factors, could more efficiently help the understanding of GAD pathogenesis. We investigated the relationship between epigenetic shifts in blood and the risk to develop GAD, evaluated by the Development and Well-Being Assessment (DAWBA) score, in 221 otherwise healthy adolescents. Our analysis focused specifically on methylation sites showing high inter-individual variation but low tissue-specific variation, in order to infer a potential correlation between results obtained in blood and brain. Two statistical methods were applied, 1) a linear model with limma and 2) a likelihood test followed by Bonferroni correction. Methylation findings were validated in a cohort of 160 adults applying logistic models against the outcome variable "anxiety treatment obtained in the past" and studied in a third cohort with regards to associated expression changes measured in monocytes. One CpG site showed 1% increased methylation in adolescents at high risk of GAD (cg16333992, P-adj. = 0.028, estimate = 3.22), as confirmed in the second cohort (p = 0.031, estimate = 1.32). The identified and validated CpG site is located within the STK32B promoter region and its methylation level was positively associated with gene expression. Gene ontology analysis revealed that STK32B is involved in stress response and defense response. Our results provide evidence that shifts in DNA methylation are associated with a modulated risk profile for GAD in adolescence.

Keywords
Epigenetics, DNA methylation, Generalized anxiety disorder, STK32B
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-361546 (URN)10.1016/j.jpsychires.2018.03.008 (DOI)000438660500008 ()29604450 (PubMedID)
Available from: 2018-10-08 Created: 2018-10-08 Last updated: 2018-10-08Bibliographically approved
Mårtensson, J., Lätt, J., Åhs, F., Fredriksson, M., Söderlund, H., Schiöth, H. B., . . . Nilsson, M. (2018). Diffusion tensor imaging and tractography of the white matter in normal aging: The rate-of-change differs between segments within tracts. Magnetic Resonance Imaging, 45, 113-119, Article ID S0730-725X(17)30059-0.
Open this publication in new window or tab >>Diffusion tensor imaging and tractography of the white matter in normal aging: The rate-of-change differs between segments within tracts
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2018 (English)In: Magnetic Resonance Imaging, ISSN 0730-725X, E-ISSN 1873-5894, Vol. 45, p. 113-119, article id S0730-725X(17)30059-0Article in journal (Refereed) Published
Abstract [en]

Knowledge concerning the normal aging of cerebral white matter will improve our understanding of abnormal changes in neurodegenerative diseases. The microstructural basis of white matter maturation and aging can be investigated using diffusion tensor imaging (DTI). Generally, diffusion anisotropy increases during childhood and adolescence followed by a decline in middle age. However, this process is subject to spatial variations between tracts. The aim of this study was to investigate to what extent age-related variations also occur within tracts. DTI parameters were compared between segments of two white matter tracts, the cingulate bundle (CB) and the inferior fronto-occipital fasciculus (IFO), in 257 healthy individuals between 13 and 84years of age. Segments of the CB and the IFO were extracted and parameters for each segment were averaged across the hemispheres. The data was analysed as a function of age. Results show that age-related changes differ both between and within individual tracts. Different age trajectories were observed in all segments of the analysed tracts for all DTI parameters. In conclusion, aging does not affect white matter tracts uniformly but is regionally specific; both between and within white matter tracts.

Keywords
Tractography, Inferior fronto-occipital fasciculus, Cingulum, Aging, White matter degeneration, White matter tract
National Category
Medical and Health Sciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-319599 (URN)10.1016/j.mri.2017.03.007 (DOI)000417772500015 ()28359912 (PubMedID)
Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-02-19Bibliographically approved
Olivo, G., Latini, F., Wiemerslage, L., Larsson, E.-M. & Schiöth, H. B. (2018). Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity. Frontiers in Human Neuroscience, 12, Article ID 75.
Open this publication in new window or tab >>Disruption of Accumbens and Thalamic White Matter Connectivity Revealed by Diffusion Tensor Tractography in Young Men with Genetic Risk for Obesity
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2018 (English)In: Frontiers in Human Neuroscience, ISSN 1662-5161, E-ISSN 1662-5161, Vol. 12, article id 75Article in journal (Refereed) Published
Abstract [en]

Background: Neurovascular coupling is associated with white matter (WM) structural integrity, and it is regulated by specific subtypes of dopaminergic receptors. An altered activity of such receptors, highly expressed in reward-related regions, has been reported in carriers of obesity-risk alleles of the fat mass and obesity associated (FTO) gene. Among the reward-related regions, the thalamus and the nucleus accumbens are particularly vulnerable to blood pressure dysregulation due to their peculiar anatomo-vascular characteristics, and have been consistently reported to be altered in early-stage obesity. We have thus hypothesized that a disruption in thalamus and nucleus accumbens WM microstructure, possibly on neurovascular basis, could potentially be a predisposing factor underlying the enhanced risk for obesity in the risk-allele carriers.

Methods: We have tested WM integrity in 21 male participants genotyped on the FTO risk single nucleotide polymorphisms (SNP) rs9939609, through a deterministic tractography analysis. Only homozygous participants (9 AA, 12 TT) were included. 11 tracts were selected and categorized as following according to our hypothesis: “risk tracts”, “obesity-associated tracts”, and a control tract (forcpes major). We investigated whether an association existed between genotype, body mass index (BMI) and WM microstructural integrity in the “risk-tracts” (anterior thalamic radiation and accumbofrontal fasciculus) compared to other tracts. Moreover, we explored whether WM diffusivity could be related to specific personality traits in terms of punishment and reward sensitivity, as measure by the BIS/BAS questionnaire.

Results: An effect of the genotype and an interaction effect of genotype and BMI were detected on the fractional anisotropy (FA) of the “risk tracts”. Correlations between WM diffusivity parameters and measures of punishment and reward sensitivity were also detected in many WM tracts of both networks.

Conclusions: A disruption of the structural connectivity from the nucleus accumbens and the thalamus might occur early in carriers of the FTO AA risk-allele, and possibly act as a predisposing factor to the development of obesity.

Keywords
DTI, FTO, MRI, accumbens, obesity, thalamus, tractography, white matter
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-346993 (URN)10.3389/fnhum.2018.00075 (DOI)000425773500001 ()29520227 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-04-12Bibliographically approved
Jokinen, J., Boström, A., Dadfar, A., Ciuculete, D.-M., Chatzittofis, A., Åsberg, M. & Schiöth, H. B. (2018). Epigenetic Changes in the CRH Gene are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents. EBioMedicine, 27, 123-133, Article ID S2352-3964(17)30499-1.
Open this publication in new window or tab >>Epigenetic Changes in the CRH Gene are Related to Severity of Suicide Attempt and a General Psychiatric Risk Score in Adolescents
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2018 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 27, p. 123-133, article id S2352-3964(17)30499-1Article in journal (Refereed) Published
Abstract [en]

The aim of this study, comprising 88 suicide attempters, was to identify hypothalamic-pituitary-adrenal (HPA) -axis coupled CpG-sites showing methylation shifts linked to severity of the suicide attempt. Candidate methylation loci were further investigated as risk loci for a general psychiatric risk score in two cohorts of adolescents (cohort 1 and 2). The genome-wide methylation pattern was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. Subjects were stratified into high-risk and low-risk groups based on the severity of the suicidal behavior. We included CpG sites located within 2000 basepairs away from transcriptional start site of the following HPA-axis coupled genes: corticotropin releasing hormone (CRH), corticotropin releasing hormone binding protein (CRHBP), corticotropin releasing hormone receptor 1 (CRHR1), corticotropin releasing hormone receptor 2 (CRHR2), FK506-binding protein 51 (FKBP5) and the glucocorticoid receptor (NR3C1). The methylation state of two corticotropin releasing hormone (CRH)-associated CpG sites were significantly hypomethylated in the high-risk group of suicide attempters (n = 31) (cg19035496 and cg23409074) (p < 0.001). Adolescent cohort 1 and 2 consisted of 129 and 93 subjects, respectively, and were stratified by the in silico generated DAWBA measurements of a general psychiatric risk score into high-risk group (>~50% risk) or controls. In adolescent cohort 2, cg19035496 was hypermethylated in subjects with a high general psychiatric risk score. Our results show epigenetic changes in the CRH gene related to severity of suicide attempt in adults and a general psychiatric risk score in adolescents.

Keywords
Adolescent depression, CRH gene, Epigenetics, HPA axis, Methylation, Suicide, Suicide attempt
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-342179 (URN)10.1016/j.ebiom.2017.12.018 (DOI)000425875400017 ()29277323 (PubMedID)
Funder
Swedish Research Council, 5454; K2009-61P21304-04-4; K2009-61X-21305-01-1The Swedish Brain FoundationStockholm County Council, SLL-20150269Västerbotten County Council, VLL-582221
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-04-17Bibliographically approved
Chapman, C. D., Benedict, C. & Schiöth, H. B. (2018). Experimenter gender and replicability in science. Science Advances, 4(1), Article ID e1701427.
Open this publication in new window or tab >>Experimenter gender and replicability in science
2018 (English)In: Science Advances, ISSN 0036-8156, E-ISSN 2375-2548, Vol. 4, no 1, article id e1701427Article, review/survey (Refereed) Published
Abstract [en]

There is a replication crisis spreading through the annals of scientific inquiry. Although some work has been carried out to uncover the roots of this issue, much remains unanswered. With this in mind, this paper investigates how the gender of the experimenter may affect experimental findings. Clinical trials are regularly carried out without any report of the experimenter's gender and with dubious knowledge of its influence. Consequently, significant biases caused by the experimenter's gender may lead researchers to conclude that therapeutics or other interventions are either overtreating or undertreating a variety of conditions. Bearing this in mind, this policy paper emphasizes the importance of reporting and controlling for experimenter gender in future research. As backdrop, it explores what we know about the role of experimenter gender in influencing laboratory results, suggests possible mechanisms, and suggests future areas of inquiry.

National Category
Neurosciences Psychology (excluding Applied Psychology)
Identifiers
urn:nbn:se:uu:diva-352930 (URN)10.1126/sciadv.1701427 (DOI)000426694200010 ()
Funder
Swedish Research Council
Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically approved
Machado, I., Schiöth, H. B., Lasaga, M. & Scimonelli, T. (2018). IL-1 beta reduces GluAl phosphorylation and its surface expression during memory reconsolidation and cc-melanocyte-stimulating hormone can modulate these effects. Neuropharmacology, 128, 314-323
Open this publication in new window or tab >>IL-1 beta reduces GluAl phosphorylation and its surface expression during memory reconsolidation and cc-melanocyte-stimulating hormone can modulate these effects
2018 (English)In: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 128, p. 314-323Article in journal (Refereed) Published
Abstract [en]

Pro-inflammatory cytokines can affect cognitive processes such as learning and memory. Particularly, interleukin-beta (IL-beta) influences hippocampus-dependent memories. We previously reported that administration of IL-1 beta in dorsal hippocampus impaired contextual fear memory reconsolidation. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (a-MSH). Our results also demonstrated that IL-1 beta produced a significant decrease in glutamate release from dorsal hippo campus synaptosomes after reactivation of the fear memory. Therefore, we investigated whether IL-beta administration can affect GIuA1 AMPA subunit phosphorylation, surface expression, and total expression during reconsolidation of a contextual fear memory. Also, we studied the modulatory effect of alpha-MSH. We found that IL-beta reduced phosphorylation of this subunit at Serine 831 and Serine 845 60 min after contextual fear memory reactivation. The intrahippocampal administration of IL-beta after memory reactivation also induced a decrease in surface expression and total expression of GIuA1. alpha-MSH prevented the effect of IL-beta on GIuAI phosphorylation in Serine 845, but not in Serine 831. Moreover, treatment with alpha-MSH also prevented the effect of the cytokine on GluAl surface and total expression after memory reactivation. Our results demonstrated that IL-beta regulates phosphorylation of GIuAI and may thus play an important role in modulation of AMPAR function and synaptic plasticity in the brain. These findings further illustrate the importance of IL-beta in cognition processes dependent on the hippocampus, and also reinforced the fact that alpha-MSH can reverse IL-1 beta effects on memory reconsolidation. (C) 2017 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Interleukin-1-beta (IL-1 beta), Alpha-melanocyte-stimulating hormone (alpha-MSH), Memory reconsolidation, AMPA, GluAl, p-Ser831 GluA1, p-Ser845 GIuA1, Hippocampus
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-340457 (URN)10.1016/j.neuropharm.2017.09.041 (DOI)000418977200028 ()29042315 (PubMedID)
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-02-19Bibliographically approved
Attwood, M. M., Rask-Andersen, M. & Schiöth, H. B. (2018). Orphan Drugs and Their Impact on Pharmaceutical Development. TIPS - Trends in Pharmacological Sciences, 39(6), 525-535
Open this publication in new window or tab >>Orphan Drugs and Their Impact on Pharmaceutical Development
2018 (English)In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 6, p. 525-535Article, review/survey (Refereed) Published
Abstract [en]

High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-358124 (URN)10.1016/j.tips.2018.03.003 (DOI)000432349900001 ()29779531 (PubMedID)
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7112-0921

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