Levodopa reinstates connectivity from prefrontal to premotor cortex during externally paced movement in Parkinson's disease

Dopamine deficiency affects functional integration of activity in distributed neural regions. It has been suggested that lack of dopamine induces disruption of neural interactions between prefrontal and premotor areas, which might underlie impairment of motor control observed in patients with Parkinson's disease (PD). In this study we recorded cortical activity with high-density electroencephalography in 11 patients with PD as a pathological model of dopamine deficiency, and 13 healthy control subjects. Participants performed repetitive extension-flexion movements of their right index finger, which were externally paced at a rate of 0.5 Hz. This required participants to align their movement velocity to the slow external pace. Patients were studied after at least 12-hour withdrawal of dopaminergic medication (OFF state) and after intake of the dopamine precursor levodopa (ON state) in order to examine oscillatory coupling between prefrontal and premotor areas during respectively low and high levels of dopamine. In 10 patients and 12 control participants multiple source beamformer analysis yielded task-related activation of a contralateral cortical network comprising prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA) and primary motor cortex (M1). Dynamic causal modelling was used to characterize task-related oscillatory coupling between prefrontal and premotor cortical areas. Healthy participants showed task-induced coupling from PFC to SMA, which was modulated within the γ-band. In the OFF state, PD patients did not express any frequency-specific coupling between prefrontal and premotor areas. Application of levodopa reinstated task-related coupling from PFC to SMA, which was expressed as high-β-γ coupling. Additionally, strong within-frequency γ-coupling as well as cross-frequency θ-γ coupling was observed from PFC to lPM. Enhancement of this cross-frequency θ-γ coupling after application of levodopa was positively correlated with individual improvement in motor function. The results demonstrate that dopamine deficiency impairs the ability to establish oscillatory coupling between prefrontal and premotor areas during an externally paced motor task. Application of extrinsic dopamine in PD patients reinstates physiological prefrontal-premotor coupling and additionally induces within- and cross-frequency coupling from prefrontal to premotor areas, which is not expressed in healthy participants.