Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease

Abstract

Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼ 3 and ∼ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼ 3 ms) and medium (∼ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity.

Significance statement: We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼ 3 ms) and medium (∼ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.

Keywords: deep-brain stimulation; hyperdirect pathway; intracortical circuits; motor cortical plasticity; subthalamic nucleus; transcranial magnetic stimulation.

Figure 1.

Experiment 2 setup. Three separate plasticity interventions were tested in which STN-DBS was paired with M1-TMS at 0.1 Hz for 30 min (180 pairs total). Each session varied in the ISI between DBS and TMS: Experiment 2A (short interval, ∼3 ms), Experiment 2B (medium interval, ∼23 ms), and the control interval (167 ms) were tested in each subject in a randomized order at least 1 week apart. RMT, RC (MEP amplitudes at 120%, 140%, and 160% of RMT), MEP amplitudes at fixed intensity that evoked 1 mV MEP and intracortical circuits (SICI, ICF, and LICI) were used as cortical excitability measures at baseline and at time intervals of 0–15, 15–30, and 30–45 min after the plasticity induction protocols.

Figure 2.

Example of an individual time course of M1 excitability after single-pulse STN-DBS paired with M1-TMS. Findings from patient 7 in Experiment 1 are shown. The mean MEP amplitude at each time interval after STN stimulation is expressed as a ratio to the mean baseline MEP amplitude (20 TMS pulses over the M1 adjusted to produce ∼1 mV MEP amplitude with STN-DBS switched off). Ratios >1 indicate facilitation and ratios <1 indicate inhibition of MEP amplitude. Error bars represent SEM. Two peaks of MEP facilitation were observed at 4 and 19 ms (arrows) in this patient.

Figure 3.

Effects of plasticity protocols on 1 mV MEP amplitude at the three postintervention time blocks. The data are plotted as a ratio to the baseline MEP amplitude before the plasticity protocol. Ratios >1 indicate facilitation and ratios <1 indicate inhibition. Error bars represent SEM. The plasticity protocol increased mean MEP amplitudes at short (∼3 ms) and medium (∼23 ms) ISIs, but not at the control (167 ms) interval.

Figure 4.

Effects of plasticity protocols on MEP recruitment curve at the three postintervention time blocks. The data are plotted as a ratio of the baseline MEP amplitude measured before the plasticity protocols at each stimulation intensity (expressed as percentage of RMT). Ratios >1 indicate facilitation and ratios <1 indicate inhibition. Error bars represent SEM. The results for the three plasticity interventions: short interval (∼3 ms; A); medium interval (∼23 ms; B), and control interval (167 ms; C) are shown on separate graphs. The analysis showed a trend toward significance for the intervention × stimulus intensity interaction (p = 0.07).

Figure 5.

Intracortical circuit measures at baseline and at the three postintervention time blocks. The data are plotted as a ratio of conditioned to unconditioned MEP amplitude. Ratios >1 indicate facilitation and ratios <1 indicate inhibition. Error bars represent SEM. Analysis showed a significant effect of time on SICI (A), but not on (B) or LICI (C). SICI decreased during the 15–30 min and 30–45 min postintervention time blocks after DBS-TMS pairings at short (∼3 ms), medium (∼23 ms), and control (167 ms) ISIs. *p < 0.05 compared with baseline; †p < 0.05 compared with 0–15 min.