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  • 1.
    Bernardi, R. E.
    et al.
    Heidelberg University, Germany.
    Zohsel, K.
    Heidelberg University, Germany.
    Hirth, N.
    Heidelberg University, Germany.
    Treutlein, J.
    Heidelberg University, Germany.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Laucht, M.
    Heidelberg University, Germany.
    Spanagel, R.
    Heidelberg University, Germany.
    Sommer, W. H.
    Heidelberg University, Germany.
    A gene-by-sex interaction for nicotine reward: evidence from humanized mice and epidemiology2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no e861Article in journal (Refereed)
    Abstract [en]

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

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  • 2.
    Brundin, L.
    et al.
    Van Andel Research Institute, MI 49503 USA.
    Sellgren, C. M.
    Karolinska Institute, Sweden; Broad Institute MIT and Harvard, MA USA; Massachusetts Gen Hospital, MA USA.
    Lim, C. K.
    Macquarie University, Australia.
    Grit, J.
    Van Andel Research Institute, MI 49503 USA.
    Palsson, E.
    Gothenburg University, Sweden.
    Landen, M.
    Gothenburg University, Sweden.
    Samuelsson, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry. Karolinska Institute, Sweden.
    Lundgren, Kristoffer
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Brundin, P.
    Van Andel Research Institute, MI 49503 USA.
    Fuchs, D.
    Medical University of Innsbruck, Austria.
    Postolache, T. T.
    University of Maryland, MD 21201 USA; Rocky Mt MIRECC, CO USA.
    Traskman-Bendz, L.
    Lund University, Sweden.
    Guillemin, G. J.
    Macquarie University, Australia; NHMRC Centre Research Excellence Suicide Prevent CRESP, Australia.
    Erhardt, S.
    Karolinska Institute, Sweden.
    An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no e865Article in journal (Refereed)
    Abstract [en]

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

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  • 3.
    Carvalho, Andre F.
    et al.
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Solmi, Marco
    Univ Padua, Italy; Kings Coll London, England.
    Sanches, Marcos
    Ctr Addict and Mental Hlth CAMH, Canada; Krembil Ctr NeuroInformat, Canada.
    Machado, Myrela O.
    Womens Coll Hosp, Canada.
    Stubbs, Brendon
    South London and Maudsley NHS Fdn Trust, England; Kings Coll London, England.
    Ajnakina, Olesya
    Kings Coll London, England.
    Sherman, Chelsea
    Sunnybrook Res Inst, Canada.
    Sun, Yue Ran
    Sunnybrook Res Inst, Canada.
    Liu, Celina S.
    Sunnybrook Res Inst, Canada.
    Brunoni, Andre R.
    Univ Sao Paulo, Brazil.
    Pigato, Giorgio
    Univ Padua, Italy.
    Fernandes, Brisa S.
    Univ Texas Hlth Sci Ctr Houston, TX 77030 USA.
    Bortolato, Beatrice
    Dept Mental Hlth ULSS 8 Berica, Italy.
    Husain, Muhammad I
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Dragioti, Elena
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Firth, Joseph
    Western Sydney Univ, Australia; Univ Manchester, England.
    Cosco, Theodore D.
    Simon Fraser Univ, Canada; Univ Oxford, England.
    Maes, Michael
    Chulalongkorn Univ, Thailand; Deakin Univ, Australia.
    Berk, Michael
    Deakin Univ, Australia; Orygen, Australia; Univ Melbourne, Australia; Univ Melbourne, Australia.
    Lanctot, Krista L.
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada; Sunnybrook Res Inst, Canada; Sunnybrook Res Inst, Canada; Univ Toronto, Canada.
    Vieta, Eduard
    Univ Barcelona, Spain.
    Pizzagalli, Diego A.
    Harvard Med Sch, MA 02478 USA.
    Smith, Lee
    Anglia Ruskin Univ, England.
    Fusar-Poli, Paolo
    Kings Coll London, England; South London and Maudsley Natl Hlth Serv Fdn Trust, England; Univ Pavia, Italy.
    Kurdyak, Paul A.
    Univ Toronto, Canada; Canada Inst Clin Evaluat Sci ICES, Canada; Ctr Addict and Mental Hlth CAMH, Canada.
    Fornaro, Michele
    Univ Sch Med Federico II, Italy.
    Rehm, Jurgen
    Univ Toronto, Canada; Ctr Addict and Mental Hlth CAMH, Canada; CAMH, Canada; Univ Toronto, Canada; Tech Univ Dresden, Germany; Tech Univ Dresden, Germany; Univ Toronto, Canada; IM Sechenov First Moscow State Med Univ, Russia.
    Herrmann, Nathan
    Univ Toronto, Canada; Sunnybrook Res Inst, Canada; Sunnybrook Res Inst, Canada.
    Evidence-based umbrella review of 162 peripheral biomarkers for major mental disorders2020In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 10, no 1Article, review/survey (Refereed)
    Abstract [en]

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

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  • 4.
    Gurholt, Tiril P.
    et al.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Kaufmann, Tobias
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Tubingen, Germany.
    Frei, Oleksandr
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Alnaes, Dag
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Haukvik, Unn K.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    van der Meer, Dennis
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Maastricht Univ, Netherlands.
    Moberget, Torgeir
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Oslo, Norway.
    OConnell, Kevin S.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Dahlqvist Leinhard, Olof
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. AMRA Med, Linkoping, Sweden.
    Linge, Jennifer
    AMRA Med, Linkoping, Sweden.
    Simon, Rozalyn
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine. Linköping University, Faculty of Medicine and Health Sciences. AMRA Med, Linkoping, Sweden.
    Smeland, Olav B.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Sonderby, Ida E.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Oslo Univ Hosp, Norway.
    Winterton, Adriano
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Steen, Nils Eiel
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Westlye, Lars T.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway; Univ Oslo, Norway.
    Andreassen, Ole A.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Population-based body-brain mapping links brain morphology with anthropometrics and body composition2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 295Article in journal (Refereed)
    Abstract [en]

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

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  • 5.
    Hamilton, Paul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Sacchet, Matthew D.
    Stanford Univ, CA 94305 USA.
    Hjornevik, Trine
    Oslo Univ Hosp, Norway; Norwegian Med Cyclotron Ctr, Norway; Stanford Univ, CA 94305 USA.
    Chin, Frederick T.
    Stanford Univ, CA 94305 USA.
    Shen, Bin
    Stanford Univ, CA 94305 USA.
    Kämpe, Robin
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Park, Jun Hyung
    Stanford Univ, CA 94305 USA.
    Knutson, Brian D.
    Stanford Univ, CA USA.
    Williams, Leanne M.
    Stanford Univ, CA 94305 USA.
    Borg, Nicholas
    Stanford Univ, CA USA.
    Zaharchuk, Greg
    Stanford Univ, CA 94305 USA.
    Camacho, M. Catalina
    Univ Pittsburgh, PA 15260 USA.
    Mackey, Sean
    Stanford Univ, CA 94305 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Drevets, Wayne C.
    Janssen Res and Dev LLC, NJ USA.
    Glover, Gary H.
    Stanford Univ, CA 94305 USA.
    Gambhir, Sanjiv S.
    Stanford Univ, CA 94305 USA.
    Gotlib, Ian H.
    Stanford Univ, CA USA.
    Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent C-11-raclopride positron emission tomography and functional magnetic resonance imaging investigation2018In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 8, article id 264Article in journal (Refereed)
    Abstract [en]

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

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  • 6.
    Heilig, Markus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Psykiatriska kliniken inkl beroendekliniken.
    Augier, Eric
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Pfarr, Simone
    Cent Inst Mental Hlth, Germany.
    Sommer, Wolfgang H.
    Cent Inst Mental Hlth, Germany; Cent Inst Mental Hlth, Germany.
    Developing neuroscience-based treatments for alcohol addiction: A matter of choice?2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, article id 255Article, review/survey (Refereed)
    Abstract [en]

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

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  • 7.
    Hjorth, Olof
    et al.
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Frick, Andreas
    Department of Psychology, Uppsala University and The Beijer Laboratory, Department of Medical Sciences, Psychiatry, Uppsala University, Uppsala, Sweden.
    Gingnell, Malin
    Department of Psychology, Uppsala University and Department of Medical Sciences, Psychiatry, Uppsala University, Uppsala, Sweden.
    Engman, Jonas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Björkstrand, Johannes
    Department of Psychology, Lund University, Lund, Sweden.
    Faria, Vanda
    Center for Pain and the Brain, Department of Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA and Smell & Taste Clinic, Department of Otorhinolaryngology, TU Dresden, Dresden, Germany.
    Alaie, Iman
    Department of Medical Sciences, Child and Adolescent Psychiatry, Uppsala University, Uppsala, Sweden.
    Carlbring, Per
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Jonasson, My
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Lubberink, Mark
    Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
    Antoni, Gunnar
    Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
    Reis, Margareta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences.
    Wahlstedt, Kurt
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Fredrikson, Mats
    Department of Psychology, Uppsala University, Uppsala, Sweden and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Serotonin and dopamine transporter availability in social anxiety disorder after combined treatment with escitalopram and cognitive-behavioral therapy.2022In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 436Article in journal (Refereed)
    Abstract [en]

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

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  • 8.
    Hjorth, Olof R.
    et al.
    Uppsala Univ, Sweden.
    Frick, Andreas
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Gingnell, Malin
    Uppsala Univ, Sweden; Uppsala Univ, Sweden.
    Hoppe, Johanna M.
    Uppsala Univ, Sweden.
    Faria, Vanda
    Uppsala Univ, Sweden; Harvard Med Sch, MA 02115 USA; Tech Univ Dresden, Germany.
    Hultberg, Sara
    Uppsala Univ, Sweden.
    Alaie, Iman
    Uppsala Univ, Sweden.
    Mansson, Kristoffer N. T.
    Karolinska Inst, Sweden; Max Planck Inst Human Dev, Germany; Max Planck UCL Ctr Computat Psychiat & Ageing Res, England.
    Rosen, Jorgen
    Uppsala Univ, Sweden.
    Reis, Margareta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology. Linköping University, Faculty of Medicine and Health Sciences. Skane Univ Hosp, Sweden.
    Wahlstedt, Kurt
    Uppsala Univ, Sweden.
    Jonasson, My
    Uppsala Univ, Sweden.
    Lubberink, Mark
    Uppsala Univ, Sweden.
    Antoni, Gunnar
    Uppsala Univ, Sweden.
    Fredrikson, Mats
    Uppsala Univ, Sweden; Karolinska Inst, Sweden.
    Furmark, Tomas
    Uppsala Univ, Sweden.
    Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 559Article in journal (Refereed)
    Abstract [en]

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

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  • 9.
    Javaheripour, Nooshin
    et al.
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Li, Meng
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Chand, Tara
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany.
    Krug, Axel
    Univ Bonn, Germany; Philipps Univ Marburg, Germany.
    Kircher, Tilo
    Philipps Univ Marburg, Germany.
    Dannlowski, Udo
    Univ Munster, Germany.
    Nenadic, Igor
    Philipps Univ Marburg, Germany.
    Hamilton, Paul
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Sacchet, Matthew D.
    Harvard Med Sch, MA USA.
    Gotlib, Ian H.
    Stanford Univ, CA 94305 USA.
    Walter, Henrik
    Charite Univ Med Berlin, Germany; Free Univ Berlin, Germany; Berlin Inst Hlth, Germany; Humboldt Univ, Germany.
    Frodl, Thomas
    Otto von Guericke Univ, Germany.
    Grimm, Simone
    Charite Univ Med Berlin, Germany.
    Harrison, Ben J.
    Univ Melbourne, Australia.
    Wolf, Christian Robert
    Heidelberg Univ, Germany.
    Olbrich, Sebastian
    Dept Psychiat Psychotherapy & Psychosomat, Switzerland.
    van Wingen, Guido
    Univ Amsterdam, Netherlands.
    Pezawas, Lukas
    Med Univ Vienna, Austria.
    Parker, Gordon
    Univ New South Wales, Australia.
    Hyett, Matthew P.
    Univ Western Australia, Australia.
    Saemann, Philipp G.
    Max Planck Inst Psychiat, Germany.
    Hahn, Tim
    Univ Munster, Germany.
    Steinstraeter, Olaf
    Philipps Univ Marburg, Germany.
    Jansen, Andreas
    Philipps Univ Marburg, Germany; Philipps Univ Marburg, Germany.
    Yuksel, Dilara
    SRI Int, CA USA.
    Kämpe, Robin
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Davey, Christopher G.
    Univ Melbourne, Australia.
    Meyer, Bernhard
    Med Univ Vienna, Austria.
    Bartova, Lucie
    Med Univ Vienna, Austria.
    Croy, Ilona
    Friedrich Schiller Univ Jena, Germany; Tech Univ Dresden, Germany.
    Walter, Martin
    Jena Univ Hosp, Germany; Clin Affect Neuroimaging Lab CANLAB, Germany; Leibniz Inst Neurobiol, Germany; Univ Tubingen, Germany.
    Wagner, Gerd
    Jena Univ Hosp, Germany.
    Altered resting-state functional connectome in major depressive disorder: a mega-analysis from the PsyMRI consortium2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 511Article in journal (Refereed)
    Abstract [en]

    Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers (). After applying strict exclusion criteria, the final sample consisted of 606 MDD patients (age: 35.8 +/- 11.9 y.o.; females: 60.7%) and 476 healthy participants (age: 33.3 +/- 11.0 y.o.; females: 56.7%). We found significant relative hypoconnectivity within somatosensory motor (SMN), salience (SN) networks and between SMN, SN, dorsal attention (DAN), and visual (VN) networks in MDD patients. No significant differences were detected within the default mode (DMN) and frontoparietal networks (FPN). In addition, alterations in network organization were observed in terms of significantly lower network segregation of SMN in MDD patients. Although medicated patients showed significantly lower FC within DMN, FPN, and SN than unmedicated patients, there were no differences between medicated and unmedicated groups in terms of network organization in SMN. We conclude that the network organization of cortical networks, involved in processing of sensory information, might be a more stable neuroimaging marker for MDD than previously assumed alterations in higher-order neural networks like DMN and FPN.

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  • 10.
    Korhonen, Laura
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Paul, Elisabeth
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wåhlén, Karin
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Haring, Liina
    5 Institute of Clinical Medicine University of Tartu; Psychiatry Clinic of Tartu University Hospital, Tartu, Estonia.
    Vasar, Eero
    Institute of Biomedicine and Translational Medicine, University of Tartu, Estonia.
    Vaheri, Antti
    7 Department of Virology, Medicum, University of Helsinki, Finland.
    Lindholm, Dan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Department of Biochemistry and Developmental Biology, Medicum, University of Helsinki, Finland; 9 Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Finland.
    Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 326Article in journal (Refereed)
    Abstract [en]

    Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

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  • 11.
    Mansson, Kristoffer N. T.
    et al.
    Karolinska Inst, Sweden; Stockholm Univ, Sweden; Uppsala Univ, Sweden.
    Lindqvist, Daniel
    Lund Univ, Sweden.
    Yang, Liu L.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Svanborg, Cecilia
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Isung, Josef
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Nilsonne, Gustav
    Karolinska Inst, Sweden; Stockholm Univ, Sweden.
    Bergman-Nordgren, Lise
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    El Alaoui, Samir
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Hedman-Lagerlof, Erik
    Karolinska Inst, Sweden.
    Kraepelien, Martin
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Hogstrom, Jens
    Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Inst, Sweden; Stockholm Hlth Care Serv, Sweden.
    Boraxbekk, Carl-Johan
    Umea Univ, Sweden; Copenhagen Univ Hosp, Denmark.
    Fischer, Hakan
    Stockholm Univ, Sweden.
    Lavebratt, Catharina
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Wolkowitz, Owen M.
    Univ Calif San Francisco, CA USA.
    Furmark, Tomas
    Uppsala Univ, Sweden.
    Improvement in indices of cellular protection after psychological treatment for social anxiety disorder2019In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 9, no 1, article id 340Article in journal (Refereed)
    Abstract [en]

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

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  • 12.
    Månsson, Kristoffer N T
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Frick, A
    Uppsala Univ, Dept Psychol, Uppsala, Sweden.
    Boraxbekk, C-J
    Umea Univ, Umea, Sweden.
    Marquand, A F
    Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands, Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London, England.
    Williams, S C R
    Kings Coll London, Inst Psychiat, Ctr Neuroimaging Sci, Dept Neuroimaging, London WC2R 2LS, England.
    Carlbring, P
    Stockholm Univ, Dept Psychol, S-10691 Stockholm, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences.
    Furmark, T
    Uppsala Univ, Dept Psychol, Uppsala, Sweden.
    Predicting long-term outcome of Internet-delivered cognitive behavior therapy for social anxiety disorder using fMRI and support vector machine learning.2015In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 5, p. e530-Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Månsson, Kristoffer N T
    et al.
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. PRIMA Barn and Vuxenpsykiatri, Sweden.
    Salami, A.
    Karolinska Institute, Sweden; Umeå University, Sweden.
    Frick, A.
    Uppsala University, Sweden.
    Carlbring, P.
    Stockholm University, Sweden.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Karolinska Institute, Sweden.
    Furmark, T.
    Uppsala University, Sweden.
    Boraxbekk, C-J
    Umeå University, Sweden.
    Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder2016In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 6, no e727Article in journal (Refereed)
    Abstract [en]

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

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  • 14.
    Paul, Elisabeth
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Östman Vasko, Lars
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Mayberg, Helen S.
    Icahn Sch Med Mt Sinai, NY USA.
    Hamilton, J. Paul
    Univ Bergen, Norway.
    Towards a multilevel model of major depression: genes, immuno-metabolic function, and cortico-striatal signaling2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 171Article, review/survey (Refereed)
    Abstract [en]

    Biological assay and imaging techniques have made visible a great deal of the machinery of mental illness. Over fifty years of investigation of mood disorders using these technologies has identified several biological regularities in these disorders. Here we present a narrative connecting genetic, cytokine, neurotransmitter, and neural-systems-level findings in major depressive disorder (MDD). Specifically, we connect recent genome-wide findings in MDD to metabolic and immunological disturbance in this disorder and then detail links between immunological abnormalities and dopaminergic signaling within cortico-striatal circuitry. Following this, we discuss implications of reduced dopaminergic tone for cortico-striatal signal conduction in MDD. Finally, we specify some of the flaws in the current model and propose ways forward for advancing multilevel formulations of MDD most efficiently.

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  • 15.
    Pearce, Eiluned
    et al.
    UCL, England.
    Myles-Hooton, Pamela
    UCL, England.
    Johnson, Sonia
    UCL, England; Camden & Islington NHS Fdn Trust, England.
    Hards, Emily
    Univ Bath, England.
    Olsen, Samantha
    UCL, England.
    Clisu, Denisa
    UCL, England.
    Pais, Sarah M. A.
    UCL, England.
    Chesters, Heather A.
    UCL, England.
    Shah, Shyamal
    UCL, England.
    Jerwood, Georgia
    UCL, England.
    Politis, Marina
    UCL, England.
    Melwani, Joshua
    UCL, England.
    Andersson, Gerhard
    Linköping University, Department of Behavioural Sciences and Learning, Psychology. Linköping University, Faculty of Arts and Sciences. Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Shafran, Roz
    Great Ormond Street Institute of Child Health, University College London, London, UK.
    Loneliness as an active ingredient in preventing or alleviating youth anxiety and depression: a critical interpretative synthesis incorporating principles from rapid realist reviews2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 628Article, review/survey (Refereed)
    Abstract [en]

    Loneliness is a relatively common problem in young people (14-24 years) and predicts the onset of depression and anxiety. Interventions to reduce loneliness thus have significant potential as active ingredients in strategies to prevent or alleviate anxiety and depression among young people. Previous reviews have focused on quantitative evidence and have not examined potential mechanisms that could be targets for intervention strategies. To build on this work, in this review we aimed to combine qualitative and quantitative evidence with stakeholder views to identify interventions that appear worth testing for their potential effectiveness in reducing loneliness, anxiety and depression in young people aged 14-24 years, and provide insights into the potential mechanisms of action. We conducted a Critical Interpretative Synthesis, a systematic review method that iteratively synthesises qualitative and quantitative evidence and is explicitly focused on building theory through a critical approach to the evidence that questions underlying assumptions. Literature searches were performed using nine databases, and eight additional databases were searched for theses and grey literature. Charity and policy websites were searched for content relevant to interventions for youth loneliness. We incorporated elements of Rapid Realistic Review approaches by consulting with young people and academic experts to feed into search strategies and the resulting conceptual framework, in which we aimed to set out which interventions appear potentially promising in terms of theoretical and empirical underpinnings and which fit with stakeholder views. We reviewed effectiveness data and quality ratings for the included randomised controlled trials only. Through synthesising 27 studies (total participants n = 105,649; range 1-102,072 in different studies) and grey literature, and iteratively consulting with stakeholders, a conceptual framework was developed. A range of Intrapersonal (e.g. therapy that changes thinking and behaviour), Interpersonal (e.g. improving social skills), and Social Strategies (e.g. enhancing social support, and providing opportunities for social contact) seem worth testing further for their potential to help young people address loneliness, thereby preventing or alleviating depression and/or anxiety. Such strategies should be co-designed with young people and personalised to fit individual needs. Plausible mechanisms of action are facilitating sustained social support, providing opportunities for young people to socialise with peers who share similar experiences, and changing thinking and behaviour, for instance through building positive attitudes to themselves and others. The most convincing evidence of effectiveness was found in support of Intrapersonal Strategies: two randomised controlled studies quality-rated as good found decreases in loneliness associated with different forms of therapy (Cognitive Behavioural Therapy or peer network counselling), although power calculations were not reported, and effect sizes were small or missing. Strategies to address loneliness and prevent or alleviate anxiety and depression need to be co-designed and personalised. Promising elements to incorporate into these strategies are social support, including from peers with similar experiences, and psychological therapy.

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  • 16.
    Perini, Irene
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Gustafsson, Per
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Igelström, Kajsa
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jasiunaite Jokubaviciene, Brigita
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Kämpe, Robin
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Mayo, Leah
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Molander, Johanna
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Olausson, Håkan
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Clinical Neurophysiology. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Zetterqvist, Maria
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Department of Child and Adolescent Psychiatry in Linköping.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Altered relationship between subjective perception and central representation of touch hedonics in adolescents with autism-spectrum disorder2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 224Article in journal (Refereed)
    Abstract [en]

    An impairment of social communication is a core symptom of autism-spectrum disorder (ASD). Affective touch is an important means of social interaction, and C-Tactile (CT) afferents are thought to play a key role in the peripheral detection and encoding of these stimuli. Exploring the neural and behavioral mechanisms for processing CT-optimal touch (similar to 3 cm/s) may therefore provide useful insights into the pathophysiology of ASD. We examined the relationship between touch hedonics (i.e. the subjective pleasantness with which affective touch stimuli are perceived) and neural processing in the posterior superior temporal sulcus (pSTS). This region is less activated to affective touch in individuals with ASD, and, in typically developing individuals (TD), is correlated positively with touch pleasantness. TD and ASD participants received brushing stimuli at CT-optimal, and CT-non-optimal speeds during fMRI. Touch pleasantness and intensity ratings were collected, and affective touch awareness, a measure of general touch hedonics was calculated. As expected, slow touch was perceived as more pleasant and less intense than fast touch in both groups, whereas affective touch awareness was moderately higher in TD compared to ASD. There was a strong, positive correlation between right pSTS activation and affective touch awareness in TD, but not in ASD. Our findings suggest that altered neural coupling between right pSTS and touch hedonics in ASD may be associated with social touch avoidance in ASD.

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  • 17.
    Serpeloni, F.
    et al.
    University of Konstanz, Germany.
    Radtke, K.
    University of Konstanz, Germany; University of Konstanz, Germany.
    de Assis, S. G.
    Fundacao Oswaldo Cruz, Brazil.
    Henning, F.
    University of Federal Rio de Janeiro, Brazil.
    Nätt, Daniel
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Elbert, T.
    University of Konstanz, Germany.
    Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study2017In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 7, article id e1202Article in journal (Refereed)
    Abstract [en]

    Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR amp;lt; 0.05) associated with the grandmothers report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDRo0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems.

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  • 18.
    Van Booven, Derek
    et al.
    Univ Miami, FL 33136 USA.
    Li, Mengying
    Univ Miami, FL 33136 USA.
    Rao, J. Sunil
    Univ Miami, FL 33136 USA.
    Blokhin, Ilya O.
    Univ Miami, FL 33136 USA; Jackson Mem Hosp, FL 33136 USA.
    Mayfield, R. Dayne
    Univ Texas Austin, TX 78712 USA.
    Barbier, Estelle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Wahlestedt, Claes
    Univ Miami, FL 33136 USA.
    Alcohol use disorder causes global changes in splicing in the human brain2021In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 2Article in journal (Refereed)
    Abstract [en]

    Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.

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  • 19.
    Xue, Pei
    et al.
    Uppsala Univ, Sweden.
    Merikanto, Ilona
    Univ Helsinki, Finland.
    Chung, Frances
    Univ Toronto, Canada.
    Morin, Charles M.
    Univ Laval, Canada.
    Espie, Colin
    Univ Oxford, England.
    Bjorvatn, Bjorn
    Univ Bergen, Norway; Haukeland Hosp, Norway.
    Cedernaes, Jonathan
    Uppsala Univ, Sweden; Uppsala Univ, Sweden; Northwestern Univ, IL USA.
    Landtblom, Anne-Marie
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
    Penzel, Thomas
    Charite, Germany.
    De Gennaro, Luigi
    Sapienza Univ Rome, Italy; IRCCS Fdn Santa Lucia, Italy.
    Holzinger, Brigitte
    Med Univ Vienna, Austria.
    Matsui, Kentaro
    Natl Ctr Hosp, Japan.
    Hrubos-Strom, Harald
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Korman, Maria
    Ariel Univ, Israel.
    Leger, Damien
    Hop Hotel Dieu Paris, France; Univ Paris, France.
    Mota-Rolim, Sergio
    Onofre Lopes Univ Hosp, Brazil; Univ Fed Rio Grande do Norte, Brazil.
    Bolstad, Courtney J.
    Mississippi State Univ, MS USA.
    Nadorff, Michael
    Mississippi State Univ, MS USA.
    Plazzi, Giuseppe
    IRCCS Ist Sci Neurol Bologna, Italy; Univ Modena & Reggio Emilia, Italy.
    Reis, Catia
    Univ Catolica Portuguesa, Portugal; Univ Lisbon, Portugal; Univ Lisbon, Portugal.
    Chan, Rachel Ngan Yin
    Chinese Univ Hong Kong, Peoples R China.
    Wing, Yun Kwok
    Chinese Univ Hong Kong, Peoples R China.
    Yordanova, Juliana
    Bulgarian Acad Sci, Bulgaria.
    Bjelajac, Adrijana Koscec
    Inst Med Res & Occupat Hlth, Croatia.
    Inoue, Yuichi
    Tokyo Med Univ, Japan; Japan Somnol Ctr, Japan.
    Partinen, Markku
    Univ Helsinki, Finland; Terveystalo Healthcare Serv, Finland.
    Dauvilliers, Yves
    Univ Montpellier, France.
    Benedict, Christian
    Uppsala Univ, Sweden.
    Persistent short nighttime sleep duration is associated with a greater post-COVID risk in fully mRNA-vaccinated individuals2023In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 32Article in journal (Refereed)
    Abstract [en]

    Short nighttime sleep duration impairs the immune response to virus vaccination, and long nighttime sleep duration is associated with poor health status. Thus, we hypothesized that short (<6 h) and long (>9 h) nighttime sleepers have a higher post-COVID risk than normal nighttime sleepers, despite two doses of mRNA vaccine (which has previously been linked to lower odds of long-lasting COVID-19 symptoms). Post-COVID was defined as experiencing at least one core COVID-19 symptom for at least three months (e.g., shortness of breath). Multivariate logistic regression adjusting for age, sex, BMI, and other factors showed in 9717 respondents (age span 18-99) that two mRNA vaccinations lowered the risk of suffering from post-COVID by about 21% (p < 0.001). When restricting the analysis to double-vaccinated respondents (n = 5918), short and long sleepers exhibited a greater post-COVID risk than normal sleepers (adjusted OR [95%-CI], 1.56 [1.29, 1.88] and 1.87 [1.32, 2.66], respectively). Among respondents with persistent sleep duration patterns during the pandemic compared to before the pandemic, short but not long sleep duration was significantly associated with the post-COVID risk (adjusted OR [95%-CI], 1.59 [1.24, 2.03] and 1.18 [0.70, 1.97], respectively). No significant association between sleep duration and post-COVID symptoms was observed in those reporting positive SARS-CoV-2 test results (n = 538). Our findings suggest that two mRNA vaccinations against SARS-CoV-2 are associated with a lower post-COVID risk. However, this protection may be less pronounced among those sleeping less than 6 h per night. Our findings warrant replication in cohorts with individuals with confirmed SARS-CoV-2 infection.

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