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Frick, A., Engman, J., Wahlstedt, K., Gingnell, M., Fredrikson, M. & Furmark, T. (2018). Anterior cingulate cortex activity as a candidate biomarker for treatment selection in social anxiety disorder. BJPsych bulletin, 4(3)
Open this publication in new window or tab >>Anterior cingulate cortex activity as a candidate biomarker for treatment selection in social anxiety disorder
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2018 (English)In: BJPsych bulletin, ISSN 2056-4694, E-ISSN 2056-4708, Vol. 4, no 3Article in journal (Refereed) Published
Abstract [en]

We aimed to identify biomarkers to guide the decision to add selective serotonin reuptake inhibitors (SSRI) to psychological treatment for social anxiety disorder (SAD). Forty-eight patients with SAD underwent functional magnetic resonance imaging and collection of clinical and demographic variables before treatment with cognitive–behavioural therapy, combined on a double-blind basis with either escitalopram or placebo for 9 weeks. Pre-treatment neural reactivity to aversive faces in the dorsal anterior cingulate cortex (ACC), but not clinical/demographic variables, moderated clinical outcomes. Cross-validated individual-level predictions accurately identified 81% of responders/non-responders. Dorsal ACC reactivity is thus a potential biomarker for SAD treatment selection.

Place, publisher, year, edition, pages
Cambridges Institutes Press, 2018
Keywords
Functional magnetic resonance imaging, anxiety, prediction, selective serotonin reuptake inhibitors, cognitive–behavioural therapy, social phobia
National Category
Psychology Psychiatry
Identifiers
urn:nbn:se:uu:diva-353596 (URN)10.1192/bjo.2018.15 (DOI)000436933400012 ()29922481 (PubMedID)
Funder
Swedish Research CouncilRiksbankens JubileumsfondThe Swedish Brain FoundationForte, Swedish Research Council for Health, Working Life and WelfareSwedish Society for Medical Research (SSMF)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-08-31Bibliographically approved
Frick, A. (2017). Common and Distinct Gray Matter Alterations in Social Anxiety Disorder and Major Depressive Disorder. EBioMedicine, 21, 53-54
Open this publication in new window or tab >>Common and Distinct Gray Matter Alterations in Social Anxiety Disorder and Major Depressive Disorder
2017 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 21, p. 53-54Article in journal, Editorial material (Other academic) Published
National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-328070 (URN)10.1016/j.ebiom.2017.06.021 (DOI)000409430700013 ()28651853 (PubMedID)
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-03-16Bibliographically approved
Jonasson, M., Appel, L., Danfors, T., Nyholm, D., Askmark, H., Frick, A., . . . Lubberink, M. (2017). Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.. American Journal of Nuclear Medicine and Molecular Imaging, 7(6), 263-274
Open this publication in new window or tab >>Development of a clinically feasible [11C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.
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2017 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 7, no 6, p. 263-274Article in journal (Refereed) Published
Abstract [en]

[11C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [11C]PE2I scans, showing dopamine transporter availability (BPND) and relative cerebral blood flow (R1), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application. Twelve subjects with parkinsonism and seventeen healthy controls underwent 80 min dynamic [11C]PE2I PET scans. BPND and R1 images were generated using cerebellum reference region defined on a co-registered MRI, as well as a supervised cluster analysis (SVCA)-based reference. Initial 20, 30 and 40 min of the scans were extracted and images of standardized uptake value ratio (SUVR) and R1 were computed using MRI- and SVCA-based reference. Correlation was high between striatal 80 min MRI-based BPND and 40 min SVCA-based SUVR-1 (R2=0.95). High correlation was also found between R1 values in striatal and limbic regions (R2≥0.91) whereas correlation was moderate for cortical regions (R2=0.71). The results indicate that dynamic [11C]PE2I scans can be restricted to 40 min and that SVCA can be used for automatic extraction of a reference region. These outcomes will support routine applications of [11C]PE2I PET in clinical settings.

Keywords
PET, [11C]PE2I, parametric images, parkinsonism, supervised clustering
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-340790 (URN)000419593300003 ()29348981 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)
Available from: 2018-02-02 Created: 2018-02-02 Last updated: 2018-02-21Bibliographically approved
Faria, V., Gingnell, M., M. Hoppe, J., Hjorth, O., Alaie, I., Frick, A., . . . Furmark, T. (2017). Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial. EBioMedicine (24), 179-188, Article ID S2352-3964(17)30385-7.
Open this publication in new window or tab >>Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial
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2017 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, no 24, p. 179-188, article id S2352-3964(17)30385-7Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD).

METHODS: We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605.

FINDINGS: Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n=24) as compared to covert (n=22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69-31.65, p<0.0001) with more than three times higher response rate (50% vs. 14%; χ(2)(1)=6.91, p=0.009) and twice the effect size (d=2.24 vs. d=1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p≤0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p=0.0006) and attenuated amygdala (z threshold 2.70, p=0.003) activity.

INTERPRETATION: The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy.

FUNDING RESOURCES: The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond - the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).

Keywords
Expectancies, Neuroimaging, Placebo effect, SSRI, Social anxiety disorder, fMRI
National Category
Psychology General Practice
Identifiers
urn:nbn:se:uu:diva-331755 (URN)10.1016/j.ebiom.2017.09.031 (DOI)000414392900030 ()29033138 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2011-1368Swedish Research Council, 421-2013-1366Riksbankens Jubileumsfond, P13-1270:1
Note

Vanda Faria and Malin Gingnell contributed equally

Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2018-02-12Bibliographically approved
Frick, A. (2017). Increased serotonin 1A receptor availability in the raphe nuclei predicts future suicidal behaviour. Evidence-Based Mental Health, 20(3), E11
Open this publication in new window or tab >>Increased serotonin 1A receptor availability in the raphe nuclei predicts future suicidal behaviour
2017 (English)In: Evidence-Based Mental Health, ISSN 1362-0347, E-ISSN 1468-960X, Vol. 20, no 3, p. E11-Article in journal, Editorial material (Other academic) Published
National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-328071 (URN)10.1136/eb-2017-102650 (DOI)
Note

ABSTRACT FROM: Oquendo MA, Galfalvy H, Sullivan GM, et al. Positron emission tomographic imaging of the serotonergic system and prediction of risk and lethality of future suicidal behavior. JAMA Psychiatry 2016;73:1048–55.

Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-03-15Bibliographically approved
Heurling, K., Leuzy, A., Jonasson, M., Frick, A., Zimmer, E. R., Nordberg, A. & Lubberink, M. (2017). Quantitative positron emission tomography in brain research. Brain Research, 1670, 220-234, Article ID S0006-8993(17)30270-6.
Open this publication in new window or tab >>Quantitative positron emission tomography in brain research
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2017 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1670, p. 220-234, article id S0006-8993(17)30270-6Article, review/survey (Refereed) Published
Abstract [en]

The application of positron emission tomography (PET) in brain research has increased substantially during the past 20 years, and is still growing. PET provides a unique insight into physiological and pathological processes in vivo. In this article we introduce the fundamentals of PET, and the methods available for acquiring quantitative estimates of the parameters of interest. A short introduction to different areas of application is also given, including basic research of brain function and in neurology, psychiatry, drug receptor occupancy studies, and its application in diagnostics of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Our aim is to inform the unfamiliar reader of the underlying basics and potential applications of PET, hoping to inspire the reader into considering how the technique could be of benefit for his or her own research.

Keywords
Brain, Diagnostics, Imaging biomarkers, Molecular imaging, Positron emission tomography
National Category
Neurosciences Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-326069 (URN)10.1016/j.brainres.2017.06.022 (DOI)000407666000024 ()28652218 (PubMedID)
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2018-01-13Bibliographically approved
Bas-Hoogendam, J. M., van Steenbergen, H., Pannekoek, J. N., Fouche, J.-P., Lochner, C., Hattingh, C. J., . . . van der Wee, N. J. J. (2017). Sample Size Matters: A Voxel-Based Morphometry Multi-Center Mega-Analysis of Gray Matter Volume in Social Anxiety Disorder. Paper presented at 72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA. Biological Psychiatry, 81(10), S7-S8
Open this publication in new window or tab >>Sample Size Matters: A Voxel-Based Morphometry Multi-Center Mega-Analysis of Gray Matter Volume in Social Anxiety Disorder
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2017 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 81, no 10, p. S7-S8Article in journal, Meeting abstract (Other academic) Published
Keywords
Social Anxiety Disorder, Voxel Based Morphometry
National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-331803 (URN)10.1016/j.biopsych.2017.02.027 (DOI)000400348700017 ()
Conference
72nd Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry (SOBP), MAY 18-20, 2017, San Diego, CA
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and WelfareEU, FP7, Seventh Framework Programme
Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2017-10-19Bibliographically approved
Björkstrand, J., Ågren, T., Åhs, F., Frick, A., Larsson, E.-M., Hjorth, O., . . . Fredrikson, M. (2017). Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear. Behavioural Brain Research, 324, 125-129
Open this publication in new window or tab >>Think twice, it's all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
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2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 324, p. 125-129Article in journal (Refereed) Published
Abstract [en]

Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10 min, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6 h after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10 min than the 6 h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10 min than the 6 h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

Keywords
Reconsolidation disruption, Extinction, Exposure therapy, Amygdala, Approach behavior, Spider fear
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-315854 (URN)10.1016/j.bbr.2017.02.016 (DOI)000397691100016 ()28214541 (PubMedID)
Funder
Swedish Research Council, 2013-2825, 2012-00804The Swedish Brain Foundation, F02014-0151
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-06-26Bibliographically approved
Bas-Hoogendam, J. M., van Steenbergen, H., Pannekoek, J. N., Fouche, J.-P., Lochner, C., Hattingh, C. J., . . . van der Wee, N. J. A. (2017). Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder. NeuroImage: Clinical, 16, 678-688
Open this publication in new window or tab >>Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder
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2017 (English)In: NeuroImage: Clinical, ISSN 0353-8842, E-ISSN 2213-1582, Vol. 16, p. 678-688Article in journal (Refereed) Published
Abstract [en]

Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric comorbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in graymatter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multisite imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples. An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n = 174) and healthy control (HC)-participants (n = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.

Keywords
Social anxiety disorder, Structural MRI, Voxel-based morphometry, Gray matter, Mega-analysis, Striatum
National Category
Radiology, Nuclear Medicine and Medical Imaging Neurology
Identifiers
urn:nbn:se:uu:diva-340172 (URN)10.1016/j.nicl.2017.08.001 (DOI)000413235100071 ()
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Research CouncilForte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-01-26 Created: 2018-01-26 Last updated: 2018-01-26Bibliographically approved
Gingnell, M., Frick, A., Engman, J., Alaie, I., Björkstrand, J., Faria, V., . . . Furmark, T. (2016). Combining escitalopram and cognitive-behavioural therapy for social anxiety disorder: randomised controlled fMRI trial.. British Journal of Psychiatry, 209(3), 229-235
Open this publication in new window or tab >>Combining escitalopram and cognitive-behavioural therapy for social anxiety disorder: randomised controlled fMRI trial.
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2016 (English)In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 209, no 3, p. 229-235Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) are often used concomitantly to treat social anxiety disorder (SAD), but few studies have examined the effect of this combination.

AIMS: To evaluate whether adding escitalopram to internet-delivered CBT (ICBT) improves clinical outcome and alters brain reactivity and connectivity in SAD.

METHOD: Double-blind, randomised, placebo-controlled neuroimaging trial of ICBT combined either with escitalopram (n = 24) or placebo (n = 24), including a 15-month clinical follow-up (trial registration: ISRCTN24929928).

RESULTS: Escitalopram+ICBT, relative to placebo+ICBT, resulted in significantly more clinical responders, larger reductions in anticipatory speech state anxiety at post-treatment and larger reductions in social anxiety symptom severity at 15-month follow-up and at a trend-level (P = 0.09) at post-treatment. Right amygdala reactivity to emotional faces also decreased more in the escitalopram+ICBT combination relative to placebo+ICBT, and in treatment responders relative to non-responders.

CONCLUSIONS: Adding escitalopram improves the outcome of ICBT for SAD and decreased amygdala reactivity is important for anxiolytic treatment response.

National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-297677 (URN)10.1192/bjp.bp.115.175794 (DOI)000383315800010 ()27340112 (PubMedID)
Available from: 2016-06-27 Created: 2016-06-27 Last updated: 2017-11-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2516-9075

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