Cortical Potentials Evoked by Subthalamic Stimulation Demonstrate a Short Latency Hyperdirect Pathway in Humans

A monosynaptic projection from the cortex to the subthalamic nucleus is thought to have an important role in basal ganglia function and in the mechanism of therapeutic subthalamic deep-brain stimulation, but in humans the evidence for its existence is limited. We sought physiological confirmation of the cortico-subthalamic hyperdirect pathway using invasive recording techniques in patients with Parkinson's disease (9 men, 1 woman). We measured sensorimotor cortical evoked potentials using a temporary subdural strip electrode in response to low-frequency deep-brain stimulation in patients undergoing awake subthalamic or pallidal lead implantations. Evoked potentials were grouped into very short latency (<2 ms), short latency (2–10 ms), and long latency (10–100 ms) from the onset of the stimulus pulse. Subthalamic and pallidal stimulation resulted in very short-latency evoked potentials at 1.5 ms in the primary motor cortex accompanied by EMG-evoked potentials consistent with corticospinal tract activation. Subthalamic, but not pallidal stimulation, resulted in three short-latency evoked potentials at 2.8, 5.8, and 7.7 ms in a widespread cortical distribution, consistent with antidromic activation of the hyperdirect pathway. Long-latency potentials were evoked by both targets, with subthalamic responses lagging pallidal responses by 10–20 ms, consistent with orthodromic activation of the thalamocortical pathway. The amplitude of the first short-latency evoked potential was predictive of the chronic therapeutic stimulation contact.

SIGNIFICANCE STATEMENT This is the first physiological demonstration of the corticosubthalamic hyperdirect pathway and its topography at high spatial resolution in humans. We studied cortical potentials evoked by deep-brain stimulation in patients with Parkinson's disease undergoing awake lead implantation surgery. Subthalamic stimulation resulted in multiple short-latency responses consistent with activation of hyperdirect pathway, whereas no such response was present during pallidal stimulation. We contrast these findings with very short latency, direct corticospinal tract activations, and long-latency responses evoked through polysynaptic orthodromic projections. These findings underscore the importance of incorporating the hyperdirect pathway into models of human basal ganglia function.

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