MULTIMODAL ASSESSMENT OF DOPAMINE SYNTHESIS AND BOLD- SIGNALING IN REWARD AND PUNISHMENT PROCESSING - A HYBRID FPET/FMRI STUDY
Authors: Schmidt *Clemens , Handschuh Patricia Anna , Reed Murray Bruce , Gomola David , Murgaš Matej , Graf Samantha , Milz Christian , Falb Pia , Nics Lukas , Eggerstorfer Benjamin , Klug Sebastian , Mayerweg Alexandra , Artmeier Lukas , Godbersen Godber Mathis , Hacker Marcus , Hahn Andreas , Lanzenberger Rupert 
Published: February 2025

Abstract

Background
The monetary incentive delay (MID) task has been regularly used to assess reward and punishment processing, especially in combination with functional magnetic resonance imaging (fMRI) [1].Previous work by our group has proposed 6-[18F]-fluoro-l-dopa (6-[18F]FDOPA) uptake as indicator of dopamine synthesis and its regulation by neuronal firing [2]. Simultaneous measurement of functional PET (fPET) and functional MRI (fMRI) parameters, as performed via a combined PET/MR scanner, allows for even more robust investigation of these parameters and their interactions, but is rarely utilised due to limited availability of scanners and the technical complexity of the measurements. Therefore, to our knowledge, there has been no published data investigating concurrent 6-[18F]FDOPA-fPET and fMRI imaging during performance of the MID task.

Aims & Objectives
To compare task-dependent changes in dopamine metabolism and glutamate-mediated signalling during performance of the MID task in healthy subjects as measured via hybrid 6- [18F]FDOPA PET/fMRI.

Method
36 (15 female, age = 23.8 ± 3.9 years) healthy subjects performed the MID task during a PET/MRI measurement with 6- [18F]FDOPA in a bolus + continuous infusion application protocol. Subjects received 400 mg entacapone and 150 mg carbidopa one hour before the start of the FDOPA application to inhibit peripheral metabolization of the tracer. Non-invasive quantification of tracer distribution was performed through acquisition of a novel image-derived input function as recently published by our group [3]. Dopamine synthesis net influx constant (Ki) of task performance was computed based on the Patlak plot, whereas fMRI β-values were estimated using SPM12. Regions of interest were extracted for nucleus accumbens, caudate nucleus, putamen and anterior insula [1]. To allow for separation between reward and punishment processing, Ki- and β-values were separated into win/loss and success/failure.
Relationships between imaging parameters were assessed via Pearson's correlation coefficient, with an additional analysis correcting for task performance as measured by won amount via partial Pearson correlation.

Results
Significant correlations were found between Ki_Loss_Accumbens and βFailure_Putamen (r = 0.69, p = 0.0004). Similarly, a slightly weaker correlation was also observed for Ki_Win_Accumbens and βSuccess_Accumbens (r = 0,48, p = 0.008). Notably, this association becomes more robust when correcting for the total amount won in the MID task (r = 0.54, p = 0.003), although this effect did not apply to the loss/failure correlation.

Discussion & Conclusion
The combination of fPET and fMRT in a single measurement allows investigators to benefit from the strengths of both modalities, specifically fPETs specificity and fMRI's temporal resolution. Through this, we were able to present task-specific correlations between Ki and β parameters in different brain regions. The correlations presented in this abstract present further evidence that the nucleus accumbens and putamen play an important role in reward processing, as has been shown in multiple previous studies [4,5].

References
1. Oldham, S. et al. (2018) ‘The anticipation and outcome phases of reward and loss processing: A neuroimaging meta-analysis of the monetary incentive delay task’, Human Brain Mapping, 39(8), pp. 3398–3418. https://doi.org/10.1002/hbm.24184.
2. Hahn, A. et al. (2021) 'Functional dynamics of dopamine synthesis during monetary reward and punishment processing’, Journal of Cerebral Blood Flow &Metabolism, 41(11), pp. 2973–2985. https://doi.org/10.1177/0271678X211019827.
3. Reed, M.B. et al. (2023) 'Validation of cardiac image derived input functions for functional PET quantification’. medRxiv, p. 2023.09.29.23296343. https://doi.org/10.1101/2023.09.29.23296343.
4. Chen, G. et al. (2023) 'Distinct reward processing by subregions of the nucleus accumbens’, Cell Reports, 42(2). https://doi.org/10.1016/j.celrep.2023.112069.
5. Haruno, M. and Kawato, M. (2006) 'Different Neural Correlates of Reward Expectation and Reward Expectation Error in the Putamen and Caudate Nucleus During Stimulus-Action-Reward Association Learning’, Journal of Neurophysiology, 95(2), pp. 948–959. https://doi.org/10.1152/jn.00382.2005.