Computational Analysis of Subthalamic Nucleus and Lenticular Fasciculus Activation During Therapeutic Deep Brain Stimulation

Abstract

The subthalamic nucleus (STN) is the most common target for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS). DBS of the globus pallidus internus (GPi) is also effective in the treatment of PD. The output fibers of the GPi that form the lenticular fasciculus pass in close proximity to STN DBS electrodes. In turn, both STN projection neurons and GPi fibers of passage represent possible therapeutic targets of DBS in the STN region. We built a comprehensive computational model of STN DBS in parkinsonian macaques to study the effects of stimulation in a controlled environment. The model consisted of three fundamental components: 1) a three-dimensional (3D) anatomical model of the macaque basal ganglia, 2) a finite element model of the DBS electrode and electric field transmitted to the tissue medium, and 3) multicompartment biophysical models of STN projection neurons, GPi fibers of passage, and internal capsule fibers of passage. Populations of neurons were positioned within the 3D anatomical model. Neurons were stimulated with electrode positions and stimulation parameters defined as clinically effective in two parkinsonian monkeys. The model predicted axonal activation of STN neurons and GPi fibers during STN DBS. Model predictions regarding the degree of GPi fiber activation matched well with experimental recordings in both monkeys. Only axonal activation of the STN neurons showed a statistically significant increase in both monkeys when comparing clinically effective and ineffective stimulation. Nonetheless, both neural targets may play important roles in the therapeutic mechanisms of STN DBS.

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…Comprehensive computer models of STN HFS in these monkeys confirmed that approximately 50% of model STN axons were activated during therapeutic stimulation (i.e., their axonal output was entrained to at least 80% of the stimulus pulses). 40 Furthermore, axonal activation of STN projection neurons was significantly higher for clinically effective than for clinically ineffective stimulation settings. These results indicate that therapeutic STN HFS activated subthalamo-pallidal projections and changed the discharge pattern of GPi neurons from an irregular to a more regular, stimulus-synchronized pattern of activity.…”

“…A computer modeling study of STN HFS in parkinsonian monkeys found that stimulation intensities, which were therapeutic for bradykinesia and rigidity, activated a significant number of these fibers. 40 Plaha et al 59 have argued that current spreading into the zona incerta, a small nucleus dorsal to the LF, also contributed to the beneficial effects of STN HFS on parkinsonian symptoms. Likewise, the reduction of tremor with STN HFS has been hypothesized to stem from direct excitation of cerebellothalamic fibers coursing through the fields of Forel.…”

Differences among implanted pulse generator waveforms cause variations in the neural response to deep brain stimulation

“…We used the monophasic waveform to illustrate the differences between the expected waveform parameters, as indicated by the programming device, and the actual waveforms produced by the IPGs (Figure 2). In our experience, explicit representation of the actual IPG waveform is an important component of accurate models of the neural response to DBS (Butson and McIntyre, 2005;Butson et al, 2006b;Miocinovic et al, 2006;Butson et al, 2007).…”

“…Both the electrode capacitance and the encapsulation layer cause increased threshold voltages. The model system is based on the concept that the primary neural targets of DBS are myelinated axons (McIntyre et al, 2004a;McIntyre et al, 2004b;Miocinovic et al, 2006). Hence, the time-and space-dependent voltage distribution generated in the tissue medium was interpolated onto multi-compartment cable-model axons to determine their activation thresholds (Butson et al, 2006a) (Figure 1C).…”

“…Hence, the time-and space-dependent voltage distribution generated in the tissue medium was interpolated onto multi-compartment cable-model axons to determine their activation thresholds (Butson et al, 2006a) (Figure 1C). This general modeling approach has been experimentally validated by examining stimulation side effects due to spillover into oculomotor nerve (Butson et al, 2006b) and corticospinal tract (Miocinovic et al, 2006;Butson et al, 2007).…”