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

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 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 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.

Association of Striatal Connectivity Gradients to Functional Domains Across Psychiatric Disorders

“…The nature of its impact on systems that are core to dysfunction in the context of psychiatric disorders explains limited disorder-specificity, while also underscoring the relevance of investigating functions over classifications. With regards to the underlying biology, we observed brain-behavioral interactions in the dominant functional gradient, where earlier work found interactions to behavior in higher-level gradients (22, 39). This indicates the complexity of the functional organization of the striatum, but also the necessity of investigating spatially overlapping patterns of connectivity in order to fully understand striatal involvement.…”

“…The latter is important because in striatum we have shown that the dominant mode of connectivity change distinguishes between caudate nucleus, nucleus accumbens and putamen, while the second mode follows a rostral-caudal gradient across the three striatal substructures (21). We have also shown that topographic connectivity in the striatum is related to complex goal-directed behaviors at the individual level (21), and shows a strong correspondence with the spatial distribution of dopaminergic projections, demonstrating their potential for investigating striatal function (22). Because connectopic maps characterize complex regions such as the striatum in a way that links to behavior, we hypothesize that individual differences in connectopic maps are predictive of psychiatric symptomatology across disorders.…”