Mapping dopaminergic projections in the human brain with resting-state fMRI

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 and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as the striatum is highly interconnected and 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 and overlapping modes of functional connectivity– can be used to map dopaminergic projections and as such, enables the investigation of dopamine-related functioning both in health and disease.

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 very high spatial correlation (r=0.884) with dopamine transporter availability –a marker of dopaminergic projections– derived from DaT-SPECT scans of 209 healthy control subjects of the Parkinson’s Progression Markers Initiative. Next, we obtained the subject-specific second-order modes from 20 controls, and 39 Parkinson’s disease patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed marker of dopamine function indeed tracks Parkinson’s disease diagnosis, symptom severity and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers of the Human Connectome Project, we establish strong associations between the second-order striatal connectivity mode and self-reported weekly use of alcohol and nicotine.

Our findings provide compelling evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in symptom severity and L-DOPA sensitivity in Parkinson’s disease patients, and exhibits strong associations with levels of nicotine and alcohol use in a population-based cohort. We hereby provide a new biomarker for dopamine-related dysfunction in the human brain with potential clinical utility that could foster insights into the neurobiological underpinnings of various dopamine-associated conditions.