FUNCTIONAL DYNAMICS OF SEROTONIN SYNTHESIS DURING MONETARY REWARD AND PUNISHMENT PROCESSING – A HYBRID FPET/FMRI STUDY
Authors: Schmidt *Clemens , Silberbauer Leo Robert , Reed Murray B , Murgas Matej , Vraka Chrysoula , Klug Sebastian , Godbersen Godber Mathis , Eggerstorfer Benjamin , Gomola David , Nics Lukas , Philippe Cecile , Hacker Marcus , Hahn Andreas , Lanzenberger Rupert 
Published: February 2025

Background

Reward processing is implicated in everyday functioning and several psychiatric conditions including major depressive disorder. The monetary incentive delay (MID) task and functional magnetic resonance imaging (fMRI) are widely used to study the neural basis of reward and punishment processing in humans (1). However, the commonly employed BOLD signal mainly represents glutamate-mediated changes in cerebral blood flow, volume and oxygenation rather than modulatory neurotransmitter action. As recently shown for the dopaminergic neurotransmitter system, functional positron emission tomography (fPET) allows to assess neurobiological underpinnings of cognitive performance on a neurotransmitter level (2). Besides dopamine, the serotonergic system plays an essential modulating role in reward processing as evidenced by preclinical and human studies (3).

Aims & Objectives

This study aimed to elucidate the serotonergic contribution to reward processing by assessing task- induced changes in α-[11C]methyl-L-tryptophan ([11C]AMT) serotonin synthesis (4) simultaneously with BOLD-derived neuronal activation.

Methods

A total of 16 healthy participants were included in this analysis. Subjects performed the MID task during a hybrid fPET/fMRI scan using a bolus plus constant infusion protocol of [11C]AMT. The Patlak plot was used to compute the net influx constant Ki as an index of serotonin synthesis for baseline and task effects. Task-induced neuronal activation was derived from the BOLD signal. Task-specific changes in serotonin synthesis rates were evaluated by one sample t-tests against zero with the nucleus accumbens being the primary region of interest. In addition, exploratory whole-brain analysis was conducted in SPM12 (p&lt;0.05 FWE corrected cluster level, p&lt;0.0001 uncorrected voxel level). Spearman correlational analyses were performed between serotonin synthesis and BOLD signal changes, corrected with the Bonferroni-Holm procedure.

Results

Increased serotonin synthesis rates during reward processing were revealed in the nucleus accumbens (Ki = 0.0014 ± 0.001, p &lt;10-4). Whole-brain analysis showed increased serotonin synthesis in the anterior insula (Ki = 0.0023 ± 0.0011, p &lt;10-6). Anterior insula serotonin synthesis correlated with BOLD-derived neuronal activation during reward anticipation (rho = -0.61, pFWE = 0.04) but not during reward feedback (rho = -0.45, pFWE = 0.16). In contrast, serotonin synthesis in the nucleus accumbens correlated with BOLD-derived neuronal activation during reward feedback (rho = -0.65, pFWE = 0.03) but not during reward anticipation (rho = 0.30, pFWE = 0.26).

Discussion & Conclusion

In this study, we assessed task-induced changes in serotonin synthesis measured by hybrid fPET/fMRI and [11C]AMT, showing robust task-specific effects in regions pivotal for reward processing (5). Thus, we introduce a novel framework for the assessment of task-specific changes in serotonin neurotransmission by synergistically amalgamating the high molecular specificity inherent to PET with the superior temporal resolution characteristic of the BOLD signal. This approach may offer a promising tool to investigate altered reward processing in psychiatric disorders.

References

1.Oldham S, Murawski C, Fornito A, Youssef G, Yü cel M, Lorenzetti V. (2018): The anticipation and outcome phases of reward and loss processing: A neuroimaging meta-analysis of the monetary incentive delay task. Hum Brain Mapp 39:3398-3418.

2.Hahn A, Reed MB, Pichler V, Michenthaler P, Rischka L, Godbersen GM, et al. (2021): Functional dynamics of dopamine synthesis during monetary reward and punishment processing. J Cereb Blood Flow Metab 41:2973-2985.

3. Kranz GS, Kasper S, Lanzenberger R. (2010): Reward and the serotonergic system. Neuroscience 166:1023-1035.

4. Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, et al. (2004): Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61:556-563.

5. Haber SN, Knutson B. (2010): The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4-26.