Abstract
The striatum receives dense dopaminergic projections, making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson's disease (PD) and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that 'connectopic mapping' - a novel approach for characterizing fine-grained, overlapping modes of functional connectivity - can be used to map dopaminergic projections in striatum. We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N = 839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a high spatial correlation (r = 0.884) with dopamine transporter availability - a marker of dopaminergic projections - derived from DaT SPECT scans of 209 healthy controls. Next, we obtained the subject-specific second-order modes from 20 controls and 39 PD patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed dopaminergic marker tracks PD diagnosis, symptom severity, and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers, we establish strong associations with self-reported alcohol and nicotine use. Our findings provide evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in PD symptom severity and L-DOPA sensitivity, and exhibits strong associations with levels of nicotine and alcohol use, thereby offering a new biomarker for dopamine-related (dys)function in the human brain.
Highlights
The brain’s dopamine system plays an important role in a wide range of behavioural and cognitive functions, including movement and reward processing [1, 2]
Connectopic mapping extracts the dominant modes of functional connectivity change within the striatum based on a Laplacian eigenmap decomposition of the similarity matrix derived from functional connectivity (i.e., Pearson correlations) computed between each striatal voxel and the rest of the brain
We demonstrated that one particular mode of functional connectivity in the striatum showed a high spatial correspondence to dopamine transporter availability (DaT), a marker of dopaminergic projections derived from Dopamine Transporter (DaT) SPECT imaging
Summary
The brain’s dopamine system plays an important role in a wide range of behavioural and cognitive functions, including movement and reward processing [1, 2]. An integral structure of the dopamine system is the striatum, which receives dense dopaminergic projections from the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the midbrain [3]. The mesolimbic pathway formed by the projections from the VTA to the NAcc has been associated with reward processing [7, 8]. Dopaminergic neurons in the VTA project to NAcc and to prefrontal cortex. These cortical projections form the mesocortical pathway associated with rewardrelated goal-directed behaviors [7, 8]
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