Tomas Furmark

The neurochemistry of shyness: Serotonin-dopamine interactions in social anxiety

Severe shyness, or social anxiety disorder (SAD), is a serious public health concern. Socially anxious behavior has been tied to exaggerated activity in the brain’s fear network and serotonin dysfunction but also to aberrant activation patterns during reward processing dependent on dopamine neurotransmission. Understanding the interaction between serotonin and dopamine synthesis is crucially important for etiologic theories of social anxiety. With the focus on serotonin-dopamine interactions, this project aims at investigating neuroimaging markers of individuals with SAD in comparison to healthy controls. A total of 48 participants, of which 24 are controls, will be recruited. All will be assessed with [11C]5-HTP and [11C]L-dopa positron emission tomography (PET), probing serotonin and dopamine synthesis respectively. In addition, participants will be scanned with functional magnetic resonance imaging (fMRI) during experimental paradigms probing fear- and reward-related neural processing. Analyses of gray and white matter structural integrity, gene polymorphisms, leukocyte telomere length and telomerase activity will also be undertaken. Finally, the accuracy of brain parameter-based classification of anxious vs. nonanxious individuals will be tested using support vector machine learning. Thus, the project uses state-of-the art imaging methods and novel data analytic approaches to answer crucially important questions regarding the cause of socially anxious behavior.
Final report
The project's purpose and development:
The project was granted funding for three years with the main aim of investigating interactions between the signaling systems for serotonin and dopamine and the brain’s activation profile during rewards and punishments in individuals suffering from social anxiety disorder (shy group) as compared to healthy diagnose-free individuals (control group). To study serotonin-dopamine interactions, the project has used positron emission tomography (PET), while brain anatomy and neural activations have been investigated with magnetic resonance imaging (MR/fMRI). Participants with social anxiety disorder have been rescanned after 9 weeks of treatment with the SSRI drug escitalopram. Blood samples for analyzes of biomarkers (e.g., gene polymorphisms and telomere length) as well as questionnaires for symptom ratings and personality variables have also been collected. The project is a follow-up to P-13-1270:1, the new research questions dealing with PET assessments of serotonin and dopamine synthesis capacity, unlike the previous project in which only the transporter proteins were investigated. The data collection has been completed, ending in May 2023.

Implementation of the project:
The project has closely followed the project plan, but the data collection has taken twice as long as expected, i.e. the project has been given an extended disposition time. The project was initially delayed due to logistics problems at the PET center at the Uppsala University Hospital. A long start-up period was required, unexpectedly, because of necessary validation of the PET tracers before the data collection could start. Also, there was an understaffing of radiochemists which made the work difficult. The availability of scanner times was also limited and we could only scan one participant at the time, one half-day per week at most. In addition, the PET data acquisition was down for long periods because tracer production did not work and troubleshooting was in progress. However, the biggest reason for the delay can be attributed to the Covid-19 pandemic with its impact on society. Nonetheless, the data collection has been completed fully in accordance with the initial intentions, ending in May 2023.

The project's three most important results:
Since the data collection with PET and fMRI has been completed just recently, there are no results available from these measurements at present. To be able to analyze PET data with parametric statistics, preprocessed images are required. These are time-consuming to produce and they will only be delivered at the end of this year (2023). Thus, regarding serotonin and dopamine synthesis capacity, and how they relate to fMRI data, results will not be available until 2024. I will be more than happy to report back on this. At the time of writing, only a compilation of clinical variables is available including the anxiolytic treatment effect of escitalopram which yielded a high effect size. However, the granted funds from Riksbankens Jubileumsfond have enabled time and resources to be spent on in-depth analyzes of collected data from P13-1270:1 and interesting results on serotonin-dopamine interactions. The three most important results are:

1. Individuals with social anxiety disorder have, in comparison to the control group, an increased availability both of serotonin and dopamine transporters in the amygdala and striatum, which are important nodes in the brain's fear and reward networks. The interaction between serotonin and dopamine transporters in these brain areas is important because there is higher correlation (co-expression) between the transporters in the social anxiety group than in the control group (Hjorth et al., Molecular Psychiatry, 2021).

2. Changes in the serotonin-dopamine balance in the brain are related to how well socially anxious individuals respond to SSRI-treatment (escitalopram), and anxiety-relief by the serotonergic drug largely depends on expectations of improvement (placebo) and its effects on dopamine transporter availability. We have studied this by comparing individuals who were informed correctly vs. incorrectly about the drug - overt vs. covert SSRI-treatment (Hjorth et al, Translational Psychiatry, 2021).

3. Pharmacological treatment with SSRI agents and psychological treatment with cognitive behavioral therapy, CBT, are both effective for social anxiety disorder, and have a dampening effect on neural activity in the amygdala. But the mechanisms of action, involving serotonin-dopamine interactions, differ. Unlike the SSRIs, CBT does not block serotonin transporters but has an effect on dopamine transporters. As in the study above, we found that altered availability of dopamine transporters correlated with improvement after treatment but the direction of the correlation differed between the SSRI (escitalopram) and CBT (Hjorth et al., Translational Psychiatry, 2022).

During the project period, thanks to support from Riksbankens Jubileumsfond, we have also been able to analyze and publish results on social anxiety disorder using other brain imaging data, biomarkers and personality variables - see the publication list. A new research question, which would complete the picture of serotonin-dopamine interactions, would be to study receptors for these neurotransmission systems with PET. However, there are many different types of receptors to consider, which complicates things.

Collaboration and making the research known:
The studies above have been published in visible international journals with peer-review and open access, and we will continue with this when the analyses of serotonin and dopamine synthesis capacity are completed. The articles are also made openly available via Uppsala University's article database DIVA. During the period, the project members participated both in national and international scientific conferences. The project manager often participates in media contexts. The research group also participates actively in the international ENIGMA project - https://enigma.ini.usc.edu/ongoing/enigma-anxiety/ which has enabled "data pooling" across international research centers primarily for measures of brain structure such as gray matter volume in individuals with social anxiety disorder. This has given rise to several publications - see the list of publications.
Grant administrator
Uppsala University
Reference number
P17-0639:1
Amount
SEK 5,049,000.00
Funding
RJ Projects
Subject
Psychology (excluding Applied Psychology)
Year
2017