Decoupling of Dopamine Release and Neural Activity in Major Depressive Disorder during Reward Processing Assessed by Simultaneous fPET-fMRI

Abstract

The interaction of the midbrain dopaminergic system and the striatum is implicated in reward processing; it is still unknown, however, how this interaction is altered in Major Depressive Disorder (MDD). In the current study, we related the dopamine release/binding inferred by [ 11 C] Raclopride functional Positron Emission Tomography (fPET) to neural activity monitored by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in adults diagnosed with MDD and healthy controls (CTL). Participants completed a monetary incentive delay (MID) task during simultaneous [ 11 C] Raclopride fPET and fMRI. Instead of the usual kinetic modeling method for analyzing dynamic PET time activity curves (TACs), we used a simpler general linear model (GLM) approach, which includes introducing a fPET dopamine activation response function to model changes in the TAC associated with the MID task. In addition, using simulations, we show that the GLM approach has several advantages over kinetic modeling. This is achieved without invoking erroneous steady-state assumptions or selecting a suitable reference region. Our results include the observation of both decreased fMRI activation and dopamine release/binding in the striatum in the MDD cohort, implying a reduced reward processing capacity in MDD. Furthermore, in the MDD group, individuals with lower fMRI activations in the right middle putamen and ventral medial prefrontal cortex (vmPFC) had higher reflection rumination scores, and individuals with lower dopamine release/binding in the left putamen and the right nucleus accumbens (NAcc) also had higher reflection rumination scores.Significant cross-modal inter-subject and intra-subject correlations of dopamine release/binding 3 and fMRI activation were observed in the CTL group, but not in the MDD group. The intrasubject correlation of the two modalities was negatively associated with reflection rumination scores in the CTL group, indicating that decoupling of the dopaminergic system and striatum may be important in the pathophysiology of MDD.

Methods for Quantifying Neurotransmitter Dynamics in the Living Brain With PET Imaging

“…For instance, the assessment of temporal changes in dopamine release has been proposed to advance to a resolution of a few minutes using detailed modeling of dopamine dynamics (Lippert et al, 2019). Furthermore, the assessment of rapid changes in dopamine release and synthesis rates during cognitive performance have also been investigated by extending the technique of functional PET (fPET) imaging using 11 C-raclopride (Zhang et al, 2019) and 18 F-FDOPA (Hahn et al, 2019).…”