606. Resting-state functional connectivity associations with dopamine synthesis

Abstract

Abstract Background Dopaminergic dysfunction and alterations in resting-state networks have been identified across overlapping psychiatric disorders. However, due to the resource-intensive nature of positron emission tomography (PET) studies, few studies have simultaneously examined associations between dopaminergic signaling and intrinsic resting-state brain activity, leaving our understanding incomplete (Conio et al., 2020; Klein et al., 2019). Metabolic connectivity mapping (MCM) (Riedl et al., 2016) specifically investigates effective connectivity as association between metabolic demands and functional connectivity. We extend this framework to the dopamine system as dopamine connectivity mapping (DA-CM) and voxel-wise estimations (Klug et al., 2022). Aims & Objectives To characterize associations between presynaptic dopamine synthesis capacity and whole-brain resting-state functional activity using multimodal PET-fMRI data. Method Twenty-nine healthy participants (10 female; mean age = 24.4 ± 5.7 years) underwent simultaneous PET/fMRI. Resting-state dopamine synthesis was quantified using 6-[18F]FDOPA PET with a cardiac image-derived input function to estimate the influx constant (Ki) (Reed et al., 2024). Concurrent resting-state fMRI data were preprocessed in SPM12, including slice-timing correction and motion correction, followed by spatial normalization to Montreal Neurological Institute space and spatial smoothing with an 8-mm full-width at half-maximum (FWHM) Gaussian kernel. Voxel-wise whole-brain functional connectivity patterns were derived for each of the dopaminergic target regions (nucleus accumbens, caudate nucleus, putamen) and spatially correlated with voxel-wise 6-[18F]FDOPA–derived Ki within each target region. This whole-brain DA-CM framework was implemented as previously described (Klug et al., 2022), yielding individual whole-brain DA-CM maps in which each voxel reflects the extent to which its functional connectivity with the target region covaries with regional dopamine synthesis capacity. For the group-level analysis, a one-sample t-test was performed across participants, with p-values corrected for multiple comparisons using a family-wise error cluster-level correction. Results Among the three dopaminergic target regions, significant DA-CM effects were observed exclusively for the caudate. Four distinct anatomical clusters survived FWE-correction and exhibited consistently increased DA-CM values across participants, indicating regions in which functional connectivity with the caudate covaried significantly with presynaptic dopamine synthesis capacity at rest. The largest cluster (pFWE < 0.001) encompassed the bilateral caudate nucleus, reflecting significant local autocorrelation. Additional clusters (all pFWE < 0.01) were located in the bilateral paracingulate gyrus and anterior cingulate cortex, as well as in the right frontal pole and orbitofrontal cortex. Discussion & Conclusions Comparison with the Yeo 7-network parcellation demonstrated that significant caudate-related DA-CM clusters overlapped predominantly with regions of the default mode network (DMN) (Yeo et al., 2011). These group-level increases indicate a systematic association between presynaptic dopamine synthesis capacity in the caudate and resting-state DMN organization, extending prior evidence linking dopaminergic midbrain activity and ventral caudate connectivity to the DMN (Choi et al., 2012; de la Cruz et al., 2021). Clinical relevance is strengthened by Parkinson’s disease research showing associations of reduced caudate 6-[18F]FDOPA uptake with cognitive impairment, underscoring striatal functional specialization (Niethammer et al., 2013). Given the involvement of the DMN in higher-order cognitive processes, and its dysfunction across multiple neuropsychiatric disorders, elucidating the specific contribution of striatal dopaminergic synthesis to DMN organization may have important clinical implications (Delaveau et al., 2010).