Neural representations of cognitive control and speech in the subthalamic nucleus

The subthalamic nucleus (STN) is a key site for control of motor function in humans. High-frequency deep-brain stimulation of the subthalamic nucleus (STN-DBS) consistently ameliorates motor symptoms of Parkinson’s disease (PD). But for unclear reasons, STN-DBS occasionally impairs cognition and/or speech in the postoperative patient. In this work, I attempt to show how the STN encodes cognitive control and speech using neural recordings from PD patients undergoing STN-DBS implantation. These results address the mechanisms of two major complications of STN-DBS.

The first set of experiments began with a novel electrical stimulation tract tracing paradigm performed in intraoperative STN-DBS patients. Suprathreshold stimulation in the human STN (>5V) resulted in antidromic short-latency evoked potentials in the prefrontal cortex, a region strongly associated with cognition. Additional intracranial electrode recordings showed that STN field potentials were coherent with 4-Hz oscillations in prefrontal cortex during performance of a simple cognitive task (fixed interval timing). These data supported the notion that a monosynaptic, cortico-STN circuit—the so-called ‘hyperdirect pathway’—played a role in cognitive control during interval timing. The specificity of the low-frequency coherence between the prefrontal cortex and STN during the timing task led to the hypothesis that low-frequency STN-DBS (4-Hz) would improve cognitive performance. Subsequent testing with postoperative STN-DBS patients showed that 12-sec fixed interval timing was more accurate with 4-Hz stimulation than with high-frequency stimulation (130-Hz) and stimulation off (0-Hz).

The second set of experiments directly compared speech- and limb movement-related modulation in individual STN neurons. A total of 28 STN neurons were isolated from 12 intraoperative STN-DBS patients who performed alternating trials of speech and contralateral limb movement. Outcome variables (firing rate, Hz; response modulation index, RMI) were calculated on a single-trial basis and regressed on a select number of fixed effects using mixed effects modeling. Modeling showed that individual STN neurons were differentially modulated by speech and limb movement. The degree to which STN neurons exhibit differentiated speech- and limb movement-related firing patterns may help predict a patient’s susceptibility to postoperative speech impairment.