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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, 220-234 p., 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.

Keyword
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, S7-S8 p.Article in journal, Meeting abstract (Other academic) Published
Keyword
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, 125-129 p.Article 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.

Keyword
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: 2017-05-16Bibliographically 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, 229-235 p.Article 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
Månsson, K. N., Salami, A., Frick, A., Carlbring, P., Andersson, G., Furmark, T. & Boraxbekk, C.-J. (2016). Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder. Translational Psychiatry, 6, Article ID e727.
Open this publication in new window or tab >>Neuroplasticity in response to cognitive behavior therapy for social anxiety disorder
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2016 (English)In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 6, e727Article in journal (Refereed) Published
Abstract [en]

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

National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-294401 (URN)10.1038/tp.2015.218 (DOI)000373892200004 ()26836415 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2017-11-30Bibliographically approved
Frick, A., Åhs, F., Michelgård Palmquist, Å., Pissiota, A., Wallenquist, U., Fernandez, M., . . . Fredrikson, M. (2016). Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study. Molecular Psychiatry, 21(10), 1400-1407.
Open this publication in new window or tab >>Overlapping expression of serotonin transporters and neurokinin-1 receptors in posttraumatic stress disorder: a multi-tracer PET study
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2016 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 21, no 10, 1400-1407 p.Article in journal (Refereed) Published
Abstract [en]

The brain serotonergic system is colocalized and interacts with the neuropeptidergic substance P/neurokinin-1 (SP/NK1) system. Both these neurochemical systems have independently been implicated in stress and anxiety, but interactions between them might be crucial for human anxiety conditions. Here, we examined the serotonin and substance P/neurokinin-1 (SP/NK1) systems individually as well as their overlapping expression in 16 patients with posttraumatic stress disorder (PTSD) and 16 healthy controls. Participants were imaged with the highly selective radiotracers [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile (DASB) and [(11)C]GR205171 assessing serotonin transporter (SERT) and NK1 receptor availability, respectively. Voxel-wise analyses in the amygdala, our a priori-defined region of interest, revealed increased number of NK1 receptors, but not SERT in the PTSD group. Symptom severity, as indexed by the Clinician-administered PTSD Scale, was negatively related to SERT availability in the amygdala, and NK1 receptor levels moderated this relationship. Exploratory, voxel-wise whole-brain analyses revealed increased SERT availability in the precentral gyrus and posterior cingulate cortex of PTSD patients. Patients, relative to controls, displayed lower degree of overlapping expression between SERT and NK1 receptors in the putamen, thalamus, insula and lateral orbitofrontal gyrus, lower overlap being associated with higher PTSD symptom severity. Expression overlap also explained more of the symptomatology than did either system individually, underscoring the importance of taking interactions between the neurochemical systems into account. Thus, our results suggest that aberrant serotonergic-SP/NK1 couplings contribute to the pathophysiology of PTSD and, consequently, that normalization of these couplings may be therapeutically important.

National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-268105 (URN)10.1038/mp.2015.180 (DOI)000384127000011 ()26619809 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationRiksbankens JubileumsfondForte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2015-12-02 Created: 2015-12-02 Last updated: 2017-12-01Bibliographically approved
Frick, A., Åhs, F., Appel, L., Jonasson, M., Wahlstedt, K., Bani, M., . . . Furmark, T. (2016). Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder. European Neuropsychopharmacology, 26(11), 1775-1783.
Open this publication in new window or tab >>Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder
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2016 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 26, no 11, 1775-1783 p.Article in journal (Refereed) Published
Abstract [en]

Abstract Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD. Eighteen SAD patients were randomized to receive daily double-blind treatment for six weeks either with the SSRI citalopram (n=6; 40 mg), the NK1R antagonist GR205171 (n=6; 5 mg; 4 weeks following 2 weeks of placebo), or placebo (n=6). Serotonin synthesis rate at rest and rCBF during stressful public speaking were assessed, before and after treatment, using positron emission tomography with the tracers [11C]5-hydroxytryptophan and [15O]water respectively. The Liebowitz Social Anxiety Scale (LSAS-SR) indexed symptom severity. All groups exhibited attenuated amygdala serotonin synthesis rate after treatment, which was associated with reduced amygdala rCBF during public speaking and accompanied by symptom improvement. These results are consistent with the notion that serotonin in the amygdala exerts an anxiogenic influence and, conversely, that anxiolysis is achieved through decreased serotonin formation in the amygdala.

Keyword
Social phobia, 5-HT, NK1, Positron emission tomography, SSRI
National Category
Psychology Neurology
Identifiers
urn:nbn:se:uu:diva-306707 (URN)10.1016/j.euroneuro.2016.09.004 (DOI)000387523600006 ()27642077 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain FoundationForte, Swedish Research Council for Health, Working Life and WelfareGlaxoSmithKline (GSK)
Available from: 2016-11-02 Created: 2016-11-02 Last updated: 2017-11-29Bibliographically approved
Furmark, T., Marteinsdottir, I., Frick, A., Heurling, K., Tillfors, M., Appel, L., . . . Fredrikson, M. (2016). Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.. Journal of Psychopharmacology, 30(10), 1028-1035.
Open this publication in new window or tab >>Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.
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2016 (English)In: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 30, no 10, 1028-1035 p.Article in journal (Refereed) Published
Abstract [en]

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.

National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-294400 (URN)10.1177/0269881116648317 (DOI)000384688900009 ()27189957 (PubMedID)
Funder
Swedish Research Council, 521-2010-3284, 521-2013-2825
Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2017-11-30Bibliographically approved
Gingnell, M., Bannbers, E., Engman, J., Frick, A., Moby, L., Wikström, J. & Sundström-Poromaa, I. (2016). The effect of combined hormonal contraceptives use on brain reactivity during response inhibition. European journal of contraception & reproductive health care, 21(2), 150-157.
Open this publication in new window or tab >>The effect of combined hormonal contraceptives use on brain reactivity during response inhibition
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2016 (English)In: European journal of contraception & reproductive health care, ISSN 1362-5187, E-ISSN 1473-0782, Vol. 21, no 2, 150-157 p.Article in journal (Refereed) Published
Abstract [en]

Objectives Cognitive control, which can be described as the ability to moderate impulses, has not previously been investigated in users of combined hormonal contraception (CHC). Given the suggested modulatory role of ovarian steroids in prefrontal dopaminergic function, which in turn taps into cognitive control, this randomised, double-blinded, placebo-controlled oral contraceptive trial set out to investigate the brain activity pattern during response inhibition in CHC users. Methods Thirty-four women were randomised to one treatment cycle with a levonorgestrel-containing CHC or placebo. The women performed a Go/NoGo task to measure brain activity during response inhibition by use of event-related functional magnetic resonance imaging (fMRI) prior to and during the CHC/placebo treatment cycle. Results No differences between CHC and placebo users in number of correct inhibitions were found during treatment, but only women on CHC significantly improved their performance between the baseline and treatment assessments. During the treatment cycle CHC users displayed decreased activity in the right middle frontal gyrus in comparison with placebo users. No other significant activations were evident between treatment groups or within groups. Conclusion Overall, CHC use had marginal effects on brain activity during response inhibition. If anything, the findings of the study may suggest reduced effort or increased efficiency in maintaining orbitofrontal cortex inhibitory cognitive control when using a combined oral contraceptive.

Keyword
Functional magnetic resonance imaging; Go/NoGo; Oestrogen; Oral contraceptives; Progestagen; Randomised clinical trial; Response inhibition
National Category
Obstetrics, Gynecology and Reproductive Medicine Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-265145 (URN)10.3109/13625187.2015.1077381 (DOI)000375025700006 ()26291330 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-10-23 Created: 2015-10-23 Last updated: 2017-12-01Bibliographically approved
Frick, A., Lubberink, M. & Furmark, T. (2016). Use of 5-Hydroxytryptophan Labeled With Carbon 11 in Social Anxiety Disorder Reply [Letter to the editor]. JAMA psychiatry, 73(2), 177-178.
Open this publication in new window or tab >>Use of 5-Hydroxytryptophan Labeled With Carbon 11 in Social Anxiety Disorder Reply
2016 (English)In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 73, no 2, 177-178 p.Article in journal, Letter (Refereed) Published
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-296904 (URN)10.1001/jamapsychiatry.2015.2751 (DOI)000371612500018 ()26720843 (PubMedID)
Available from: 2016-06-27 Created: 2016-06-20 Last updated: 2017-11-28Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2516-9075

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