Dopamine alters functional gradients in Parkinson's disease.

Neuromodulators regulate large-scale brain network topology to support adaptive behaviour. Disease models offer a unique window into how neuromodulatory systems impact large-scale brain network organisation. Here, we take advantage of Parkinson's disease-with its profound dopaminergic loss and pro-dopaminergic treatment strategies-to inform how dopamine may influence large-scale brain organisation. In 27 people with Parkinson's disease, resting-state scans were obtained on their regular dopamine medication and following overnight withdrawal of medication. Nineteen matched controls provided normative data. Gradients of brain organisation were examined using dimensionality reduction techniques. For single gradients, when individuals were on their dopamine medication, we observed a shift in higher-order networks towards somatomotor anchors. When interrogated in the multi-dimensional gradient space, we found that dopamine medication enhanced separation between functionally discrete sensory and higher-order networks. This increase in dispersion was dependent on an individual's dopamine dose level, and increased dispersion was more apparent in regions enriched with dopamine receptor (DRD2) gene expression. Together, these findings substantiate a role for dopamine in modulating large-scale functional brain organisation. Our findings further confirm that medication targeting the dopamine system may achieve its benefit by restoring aspects of network topology, and suggest new hypotheses about how dopamine medication is influencing large-scale functional brain organisation in Parkinson's disease.