Dopamine amplifies subthalamic long-latency responses to cortical stimulation in patients with Parkinson’s disease

Abstract The cortico-subthalamic hyperdirect pathway provides a rapid route for cortical influence over basal ganglia processing and is a key target of deep brain stimulation (DBS) in Parkinson’s disease (PD). However, to what degree dopamine modulates signal transmission along this pathway in humans remains unclear. Using bidirectional cortical and subthalamic electrical stimulation while invasively recording evoked responses in 15 PD patients undergoing DBS surgery, we examined cortico-subthalamic communication across dopaminergic states. Cortical stimulation evoked a short-latency subthalamic response consistent with monosynaptic hyperdirect activation that was preserved across medication conditions. In contrast, longer-latency subthalamic responses showed significant dopaminergic modulation, while cortical responses to subthalamic stimulation remained unchanged. These results reveal a temporal dissociation within the cortex–basal ganglia network, whereby fast cortical transmission is unaffected by dopamine, which in turn amplifies slower network level communication to the subthalamic nucleus. This separation of fast and delayed components provides a mechanistic framework for understanding how dopamine shapes information flow in the cortex–basal ganglia system.