Subthalamic deep brain stimulation of an anatomically detailed model of the human hyperdirect pathway

Abstract

The motor hyperdirect pathway (HDP) is considered a key target in the treatment of Parkinson's disease with subthalamic deep brain stimulation (DBS). This hypothesis is partially derived from the association of HDP activation with evoked potentials (EPs) generated in the motor cortex and subthalamic nucleus (STN) after a DBS pulse. However, the biophysical details of how and when DBS-induced action potentials (APs) in HDP neurons reach their terminations in the cortex or STN remain unclear. Therefore, we used an anatomically detailed representation of the motor HDP, as well as the internal capsule (IC), in a model of human subthalamic DBS to explore AP activation and transmission in the HDP and IC. Our results show that small diameter HDP axons exhibited AP initiation in their subthalamic terminal arbor, which resulted in relatively long transmission latencies to cortex (∼3.5-8 ms). Alternatively, large diameter HDP axons were most likely to be directly activated in the capsular region, which resulted in short transmission times to the cortex (∼1-3 ms). However, those large diameter HDP antidromic APs would be indistinguishable from any other IC axons that were also activated by the stimulus. Conversely, DBS-induced APs in both small and large diameter HDP axons reached their synaptic boutons in the STN with similar timings, but both spanned a wide temporal range (∼0.5-5 ms). We also found that using anodic or bipolar stimulation helped to bias activation of the HDP over the IC. These computational results provide useful information for linking HDP activation with EP recordings in clinical experiments.NEW & NOTEWORTHY We used biophysical models to study pathway recruitment and conduction latencies of the hyperdirect pathway (HDP) in response to subthalamic deep brain stimulation (DBS). The model system allowed us to assess the influence of increased anatomical realism on pathway activity and the possibility of identifying HDP activity in evoked potentials (EPs) recorded in either the subthalamic nucleus (STN) or cortex. The model predicts that HDP activation is accentuated by complex axonal branching in the STN.

Keywords: axon; basal ganglia; deep brain stimulation; motor cortex; subthalamic nucleus.

Graphical abstract

Figure 1.

Hyperdirect pathway. A: volumetric comparison of macaque and human brain (grayscale), primary motor cortex (M1; blue), and subthalamic nucleus (STN; green). The human brain is ∼14.4 times larger, the M1 is ∼8 times larger, and the STN is ∼7 times larger than the respective macaque analogs (22, 23). B: macaque motor corticosubthalamic axon reconstructions reported by Coudé et al. (6) which show the descending corticofugal fiber and collateralization within and throughout the (STN). Cd, caudate nucleus; ic, internal capsule; RN, red nucleus; Rt, reticular thalamus; SN, substantia nigra; Th, thalamus; ZI, zona incerta. C: motor hyperdirect pathway extracted from the Petersen human axonal pathway atlas (25).

Figure 2.

Hyperdirect pathway (HDP) arbors. A: distribution of synaptic targets of the macaque primary motor (M1) cortical hyperdirect pathway (7). B: explicitly reconstructed macaque M1 hyperdirect pathway morphologies (6). C: arborized macaque M1 hyperdirect pathway morphologies via ROOTS (21). SN, substantia nigra; STN, subthalamic nucleus; ZI, zona incerta.

Figure 3.

Methodology for hyperdirect pathway (HDP) generation. A and B: control points from the subthalamic nucleus (STN) volume and the Petersen motor HDP streamlines were spatially combined with the corticofugal fibers (CCFs). C: candidate branch points were identified on the CCFs, and control points were spatially resampled to bootstrap the volume arbors may target within the STN region. D: a bifurcation point was randomly chosen from candidates for each CCF and a cone filter was applied to the STN control points using the bifurcation point as a source and the STN motor region (dorsolateral) as a target. E: the Ruled-Optimum Ordered Tree System (ROOTS) algorithm was applied to the cone filtered control points with the bifurcation point as a source to generate new HDP terminal arbors. Right: a visual example of the Ruled-Optimum Ordered Tree System (ROOTS) generating a constrained tree through a set of predefined control points.

Figure 4.

Hyperdirect pathway (HDP) arbor statistics. A–C: morphometric comparison of generated and explicitly reconstructed HDP collaterals. The Ruled-Optimum Ordered Tree System (ROOTS) algorithm was able to generate fibers with 3.6% mean normalized root mean square error (NRMSE) for total arbor length (A), number of bifurcations (B), and bifurcation angles (C).

Figure 5.

Hyperdirect pathway (HDP) model comparison. A: Petersen motor HDP axons. B: Petersen motor HDP axons with the subthalamic nucleus (STN) volume and deep brain stimulation (DBS) electrode. C: colorized subset of 20 example arborized HDP axons. D: population of 100 arborized HDP axons. E: arborized HDP axon population with the STN volume and DBS electrode.

Figure 6.

Deep brain stimulation (DBS) recruitment curves. A, C, and E: activation thresholds for the population of internal capsule (IC; black lines), Petersen hyperdirect pathway (HDP; pink lines), and arborized HDP (light blue lines) models during DBS in the subthalamic nucleus (STN). Monopolar cathodic, monopolar anodic, and bipolar DBS were evaluated. B, D, and F: the site of action potential initiation was in either the HDP terminal arbor or in the parent corticofugal fiber in the IC. CCF, corticofugal fiber.

Figure 7.

Cortical action potential (AP) timing. Stacked histograms display the timing of action potential arrival in cortex for the internal capsule (IC) (A–C), Petersen HDP (D–F), and arborized hyperdirect pathway (HDP) (G–I) models under deep brain stimulation (DBS) delivered in three configurations: cathodal monopolar (A, D, and G), anodal monopolar (B, E, and H), and bipolar (C, F, and I). Cathodal stimulation was performed at 1 mA, anodal at 1.5 mA, and bipolar at 3.0 mA; amplitudes were selected based upon levels at which the HDP became ∼50% activated.

Figure 8.

Hyperdirect pathway (HDP) bouton action potentials (APs) in the subthalamic nucleus (STN). Stacked histograms display the time course of putative bouton action potentials within the Petersen atlas-based (A–C) and arborized (D–F) HDP models under deep brain stimulation (DBS) delivered in three configurations: cathodal monopolar (A and D), anodal monopolar (B and E), and bipolar (C and F). Cathodal stimulation was performed at 1 mA, anodal at 1.5 mA, and bipolar at 3.0 mA; amplitudes were selected based upon levels at which the HDP became ∼50% activated.