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

Abstract

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.

Keywords: DBS; cortical projections; deep-brain stimulation; electrocorticography; globus pallidus; hyperdirect pathway.

Figure 1.

Recording and stimulation locations, and invariance of EP morphology to stimulus phase reversal. A, Temporary subdural strip electrode was used to record EPs from the cortex (premotor, M1, S1, superior parietal lobule, ∼3 cm from midline) during low-frequency STN or GP DBS. Strip location was confirmed with median nerve somatosensory EP reversal (inset). White arrow indicates the central sulcus. B, C, DBS lead was implanted in the STN (B; axial slice, 4 mm below AC-PC plane) or GP (C; axial slice, at AC-PC plane) using standard microelectrode-guided technique. White arrow on MRI-CT coregistration indicates location of the lead used for evoking cortical responses. ECoG recording strip was ipsilateral to DBS lead used for stimulation. D, Changing DBS-positive contact location reversed polarity of stimulation artifact, but cortical EPs remained upgoing (Patient 1, 3.4 mA, 60 μs). Asterisks denote EP peaks at 1.6, 3, and 5 ms.

Figure 2.

Morphology of short-latency EPs evoked by STN DBS. A–C, The short-latency EP (SL-EP) contained 1–3 peaks (examples from Patients 4, 1, and 5). The first short-latency peak was defined as EP1, and the following trough as EP1 trough. EP1 peak amplitude was defined with respect to the preceding baseline. The subsequent peaks were defined as EP2 and EP3 with peak amplitude defined by the preceding trough. D, The number of short-latency EP peaks varied by cortical location and was the highest in M1 (data from all STN patients).

Figure 3.

Topographic variation in latencies and amplitudes of short-latency (2–10 ms) EPs. Latencies (top row) and amplitudes (bottom row) of EPs by recording region (mean ± SD; data from all 7 STN patients). Lines indicate statistically significant differences between M1 and other cortical regions (paired t test, significant p value 0.003 after Bonferroni correction).

Figure 4.

Very short-latency EPs (VSL-EP) can be evoked by GP or STN stimulation and are associated with an EMG response, reflecting current spread to the pyramidal tract. Very short-latency EPs (upgoing at ∼1.5 ms) were present in M1 channels during high-intensity GP DBS (A, red and black traces at high amplitudes; Patient 10, C+0–60 μs pulse width, 10 Hz) and STN DBS (B, black trace at high pulse width; Patient 6, C+1–3 mA, 10 Hz). They occurred together with EMG EPs consistent with activation of corticobulbar (C, genioglossus muscle, red and black traces; latency 10.5 ms) and corticospinal tracts (D, first dorsal interosseous muscle, black trace; latency 28 ms). Low-intensity DBS (blue traces and red trace in bottom panels) did not evoke ECoG or EMG response. The ECoG and EMG traces were recorded at the same time and are shown without smoothing. A–D, Single trial examples. E, F, Very short-latency EPs were present only in channels overlying the M1 and central sulcus (CS). There was no statistical difference in EP latency and amplitude between these two regions (mean ± SD for 3 STN and 1 GP patient).

Figure 5.

Waveforms and latencies of late occurring EPs are consistent with orthodromic activation. A, B, Typical appearance of long-latency EPs (LL-EP) in M1 from STN (A; Patient 6) and GP (B; Patient 10) using different DBS contacts (monopolar, 3 mA, 60 μs, 10 Hz). The most consistent peaks and troughs are labeled T1, P1, T2, and P2. EP1-3 refers to short-latency peaks and troughs evoked by STN DBS only. C, Comparison of latencies of long latency M1 potentials evoked by STN or GP (mean ± SD for all patients). D, Direct comparison of M1 cortical potentials evoked by STN (top) and GP DBS (bottom) in a patient with both targets implanted. Stimulation settings: STN DBS 2-1+, 3 mA, 60 μs, 2 Hz; GPi DBS 0-1+, 3.2 mA, 60 μs, 2 Hz. A, B, D, Single trial examples.

Figure 6.

Effects of changes in stimulation parameters on waveforms of short-latency EPs. Single trial examples of short-latency EP variation with changes in A, amplitude (Patient 1, 1–2 + 60 μs); B, negative contact choice (Patient 1, 1.7 mA, 60 μs); C, pulse width (Patient 4, 0–1 + 3 mA); D, monopolar versus bipolar configuration (Patient 6, 60 μs). Bipolar stimulation at 5 mA is similar to monopolar stimulation at 3 mA; E, contact polarity (Patient 1, 3.4 mA, 60 μs); and F, stimulation frequency (Patient 6, 2 + 1–3 mA, 60 μs). EP amplitude, latency, and number of peaks did not change with high- versus low-frequency stimulation.

Figure 7.

Quantitative analysis of the effects of changes in stimulation parameters on EP1 amplitude. A, EP1 amplitude at low (0.7–1 mA), medium (1.7–3 mA), and high (3.4–5 mA) stimulation current amplitude. Lines are connecting comparative trials where all other stimulation parameters were held constant. B, EP1 amplitude at four stimulation contacts (cathodes). Contact 0 was in ventral STN, contact 2 in dorsal STN, and contact 3 in zona incerta (except Patients 1 and 2 where contact 2 was also outside STN). For Patient 5, contacts 2–5 were plotted. C, EP1 amplitude at low (20–30 μs), medium (60 μs), and high (120 μs) stimulation pulse width. D, EP1 amplitude at low (10 Hz) and high (130–155 Hz) stimulation frequency. A, B, Data from only one M1 channel shown for clarity. C, D, Only three patients had comparative trials and data from only M1 channels shown for clarity. Accompanying statistics are in Table 2.

Figure 8.

Relationship between amplitude of the short-latency EP1 in M1 and eventual active contact choice for optimal motor improvement. EP1 amplitudes (from all contacts overlying M1) are grouped by negative (cathodal) stimulation contact for each STN patient. Cathodal contacts selected by a neurologist for chronic use after extensive empirical programming are indicated by green asterisks. Boxplot central mark indicates the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers, and the outliers are plotted individually.