Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease

TLDR

The study aimed to elucidate the mechanisms underlying the clinical efficacy of subthalamic nucleus deep brain stimulation in Parkinson’s disease patients. Electrophysiological recordings and microdialysis were performed in the substantia nigra pars reticulata of Parkinson’s disease patients during STN‑DBS. STN‑DBS markedly increased SNr firing, produced a 1.92–3.85 ms excitation peak, entrained neurons to the 130 Hz stimulation frequency, shifted interspike intervals toward shorter values, elevated cGMP levels, and demonstrated a stimulus‑synchronized, high‑frequency oscillatory discharge.

Abstract

Abstract To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN‐DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92–3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear‐cut increase in cyclic guanosine 3',5'‐monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus‐synchronized activation of the STN target, SNr. Our findings suggest that, during STN‐DBS, a critical change towards a high‐frequency oscillatory discharge occurs.