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Mind really does matter: The Neurobiology of Placebo-induced Anxiety Relief in Social Anxiety Disorder
Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The placebo effect, a beneficial effect attributable to a treatment containing no specific properties for the condition being treated, has been demonstrated in a variety of medical conditions. This thesis includes four studies aimed at increasing our knowledge on the neurobiology of placebo. Study I, a review of the placebo neuroimaging literature, suggested that the anterior cingulate cortex (ACC) may be a common site of action for placebo responses. However, because placebo neuroimaging studies in clinical disorders are largely lacking, the clinical relevance of this needs further clarification. The subsequent three empirical studies were thus designed from a clinical perspective. Using positron emission tomography (PET) these studies investigated the underlying neurobiology of sustained placebo responses in patients with social anxiety disorder (SAD), a disabling psychiatric condition that nonetheless may be mitigated by placebo interventions. Study II demonstrated that serotonergic gene polymorphisms affect anxiety-induced neural activity and the resultant placebo phenotype. In particular, anxiety reduction resulting from placebo treatment was tied to the attenuating effects of the TPH2 G-703T polymorphism on amygdala activity. Study III further compared the neural response profile of placebo with selective serotonin reuptake inhibitors (SSRIs), i.e the first-line pharmacological treatment for SAD. A similar anxiety reduction was noted in responders of both treatments. PET-data further revealed that placebo and SSRI responders had similar decreases of the neural response in amygdala subregions including the left basomedial/basolateral (BM/BLA) and the right ventrolateral (VLA) sections. To clarify whether successful placebo and SSRI treatments operate via similar or distinct neuromodulatory pathways, study IV focused on the connectivity patterns between the amygdala and prefrontal cortex that may be crucial for normal emotion regulation. In responders of both treatment modalities, the left amygdala (BM/BLA) exhibited negative coupling with the dorsolateral prefrontal cortex and the rostral ACC as well as a shared positive coupling with the dorsal ACC. This may represent shared treatment mechanisms involving improved emotion regulation and decreased rumination. This thesis constitutes a first step towards better understanding of the neurobiology of placebo in the treatment of anxiety, including the neural mechanisms that unite and segregate placebo and SSRI treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 92 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences, ISSN 1652-9030 ; 82
Keyword [en]
Placebo effect, anxiolysis, SAD, PET, TPH2 G-703T polymorphism, SSRIs, amygdala subregions, prefrontal cortex.
National Category
Humanities
Research subject
Psychology
Identifiers
URN: urn:nbn:se:uu:diva-181548ISBN: 978-91-554-8478-1 (print)OAI: oai:DiVA.org:uu-181548DiVA: diva2:556663
Public defence
2012-11-09, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2012-10-19 Created: 2012-09-25 Last updated: 2013-01-23Bibliographically approved
List of papers
1. Imaging the placebo response: a neurofunctional review
Open this publication in new window or tab >>Imaging the placebo response: a neurofunctional review
2008 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 18, no 7, 473-485 p.Article, review/survey (Refereed) Published
Abstract [en]

An emerging literature has started to document the neuronal changes associated with the placebo phenomenon. This has altered placebo from being considered a nuisance factor in clinical research to a target of scientific investigation per se. This paper reviews the neuroimaging literature on the placebo effect, and illustrates how imaging tools can improve current understanding of brain mechanisms underlying the placebo response. Imaging studies provide evidence of specific, predictable and replicable patterns of neural changes associated with placebo administration. In general, placebo responses seem mediated by "top-down" processes dependent on frontal cortical areas that generate and maintain cognitive expectancies. Dopaminergic reward pathways may underlie these expectancies. Placebo-induced clinical benefits also involve disorder-specific neuronal responses, yielding neurofunctional or neurochemical alterations similar to those produced by pharmacological treatments.

Keyword
Functional magnetic resonance imaging, Neuroimaging, Placebo effect, Positron emission tomography, Review
National Category
Psychology
Identifiers
urn:nbn:se:uu:diva-125736 (URN)10.1016/j.euroneuro.2008.03.002 (DOI)000257347500001 ()18495442 (PubMedID)
Available from: 2010-05-27 Created: 2010-05-27 Last updated: 2017-12-12Bibliographically approved
2. A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety
Open this publication in new window or tab >>A link between serotonin-related gene polymorphisms, amygdala activity, and placebo-induced relief from social anxiety
Show others...
2008 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 28, no 49, 13066-74 p.Article in journal (Refereed) Published
Abstract [en]

Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.

Keyword
placebo, genes, phobia, serotonin, brain, functional neuroimaging
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-102680 (URN)10.1523/JNEUROSCI.2534-08.2008 (DOI)000261378100005 ()19052197 (PubMedID)
Available from: 2009-05-11 Created: 2009-05-11 Last updated: 2017-12-13Bibliographically approved
3. Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder
Open this publication in new window or tab >>Amygdala Subregions Tied to SSRI and Placebo Response in Patients with Social Anxiety Disorder
Show others...
2012 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 37, no 10, 2222-2232 p.Article in journal (Refereed) Published
Abstract [en]

The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments, Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under double-blind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre- to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern con-elated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.

Place, publisher, year, edition, pages
Nature Publishing Group, 2012
Keyword
amygdala, SSRIs, placebo, SAD, subregions, PET
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-181544 (URN)10.1038/npp.2012.72 (DOI)000307796600005 ()
Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2017-12-07Bibliographically approved
4. Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder
Open this publication in new window or tab >>Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder
Show others...
2014 (English)In: International Journal of Neuropsychopharmacology, ISSN 1461-1457, E-ISSN 1469-5111, Vol. 17, no 8, 1149-1157 p.Article in journal (Refereed) Published
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-181547 (URN)10.1017/S1461145714000352 (DOI)000338098500004 ()
Note

Correction in: International Journal of Neuropsychopharmacology, vol. 17, issue 8, page 1353.

Available from: 2012-09-25 Created: 2012-09-25 Last updated: 2017-12-07Bibliographically approved

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