High-frequency microstimulation in human globus pallidus and substantia nigra

Abstract

Deep brain stimulation of the basal ganglia and other brain regions has been used successfully to treat a variety of neurological disorders. However, the mechanisms by which it works, remain unclear. In a previous study, we showed that locally delivered single current pulses delivered from a nearby microelectrode are sufficient to inhibit firing in the internal globus pallidus for tens of milliseconds. The GPi and the substantia nigra pars reticulata are the output nuclei of the basal ganglia and share many anatomical and physiological features. The goal of the current study was to examine the after-effects of trains of high-frequency microstimulation on neuronal firing in the GPi of Parkinson's disease and dystonia patients as well as in the SNr of PD patients. Microelectrode recordings and microstimulation were performed in a total of 57 patients during stereotactic surgery. We found that firing in the GPi and SNr is inhibited for several hundreds of milliseconds following the end of a short, 200 Hz high-frequency train delivered through the recording electrode (e.g., on average 618 ms when stimulating in the SNr with a 0.5 s train of 4 microA pulses at 200 Hz). Inhibition duration usually increased with increasing current intensity, train frequency and generally peaked for trains of 1-2 s, while it decreased with increasing train durations. Statistical analysis with general linear models revealed a significant linear relationship between current intensity and inhibition duration in all nuclei and patient groups. There was also a significant relationship between train frequency and inhibition duration in the SNr and GPi of PD patients and between train duration and inhibition duration in the GPi of PD patients. There was no significant difference in inhibition duration across patient groups but the current threshold for inhibition was significantly different in the SNr compared to the GPi. The characteristics of the inhibition observed are consistent with stimulation-induced GABA release following activation of the GABAergic afferents in the SNr and GPi. The findings suggest that high-frequency microstimulation of the GPi and SNr depresses local neuronal activity and synaptic transmission, and such mechanisms may contribute to the therapeutic effects of DBS.

Disrupting neuronal transmission: mechanism of DBS?

“…GPi-HFS at 100 Hz induced complete inhibition of 76% of neighboring neurons in normal monkeys (Chiken and Nambu, 2013), and the inhibition outlasted the stimulus period, sometimes over 100 ms after the end of stimulation. Similar post-train inhibition was also observed in Parkinsonian patients (Lafreniere-Roula et al, 2010). …”

“…In fact, neuronal firings of neighboring neurons were inhibited by STN- or GPi-DBS (Boraud et al, 1996; Dostrovsky et al, 2000; Wu et al, 2001; Filali et al, 2004; Lafreniere-Roula et al, 2010). On the other hand, recent studies have emphasized activation of neuronal elements.…”

The Multiple Correspondence Analysis Method and Brain Functional Connectivity: Its Application to the Study of the Non-linear Relationships of Motor Cortex and Basal Ganglia

“…SN and GPi showed some differences in the CC (Figures 6I,K) and in the Pearson and Spearman correlations (Figure 3) with S1 and M1 (negative relationships for the SN and no significant linking for GPi), suggesting a different functional connectivity of GPi and SN with the somatosensory and motor cortex. Although GPi and SN are frequently considered as a single entity in BG models (Albin et al, 1989; Alexander and Crutcher, 1990; Delong, 1990; Tanibuchi et al, 2009), there are biochemical (Windels et al, 2000; Kliem et al, 2007, 2010), odological (Deniau et al, 1982; Nakanishi et al, 1991; Parent et al, 1999; Mailly et al, 2003), and electrophysiological (Wichmann et al, 1999; Kaneda et al, 2005; Kliem et al, 2010; Lafreniere-Roula et al, 2010) data suggesting functional differences between them (Chastan et al, 2009; Nambu, 2011). …”

Response of Human Thalamic Neurons to High-Frequency Stimulation

“…The parameters of stimulation included variable train durations (0.5–2 s) and frequencies (0–200 Hz), as well as amplitudes (1–100 µA, but in most cases 1–5 µA). Recordings were processed using Spike 2 software (Cambridge Electronics Devices, Cambridge, UK), with further details provided in previous publications [15], [16], [17]. Because stimulation was delivered through the same electrode used for recording, it was not possible to record responses of the thalamic neurons during stimulation.…”