Associations between neuromelanin depletion and cortical rhythmic activity in Parkinson's disease

Parkinson's disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in the substantia nigra (SN) and the locus coeruleus (LC), respectively, resulting in motor and cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, the impact of reduced LC norepinephrine signaling on brain activity in PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC = 27) and task-free magnetoencephalography (NPD = 58; NHC = 65) to identify neuropathophysiological factors related to the degeneration of the LC and SN in patients with PD. We found pathological increases in rhythmic alpha (8 - 12 Hz) activity in patients with decreased LC neuromelanin, with a stronger association in patients with worse attentional impairments. This negative alpha-LC neuromelanin relationship is also stronger in fronto-motor cortices, which are regions with high densities of norepinephrine transporters in the healthy brain, and where alpha activity is negatively related to attention scores. These observations support a noradrenergic association between LC integrity and alpha band activity. Our data also show that rhythmic beta (15 - 29 Hz) activity in the left somato-motor cortex decreases with lower levels of SN neuromelanin; the same regions where beta activity reflects axial motor symptoms. Together, our findings clarify the association of well-documented alterations of rhythmic neurophysiology in PD with cortical and subcortical neurochemical systems. Specifically, attention-related alpha activity reflects dysfunction of the noradrenergic system, and beta activity with relevance to motor impairments reflects dopaminergic dysfunction.