Non-stationary discharge patterns in motor cortex under subthalamic nucleus deep brain stimulation

Sabato Santaniello,Erwin B Montgomery,Sridevi V Sarma,John T Gale

doi:10.3389/fnint.2012.00035

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) directly modulates the basal ganglia (BG), but how such stimulation impacts the cortex upstream is largely unknown. There is evidence of cortical activation in 6-hydroxydopamine (OHDA)-lesioned rodents and facilitation of motor evoked potentials in Parkinson's disease (PD) patients, but the impact of the DBS settings on the cortical activity in normal vs. Parkinsonian conditions is still debated. We use point process models to analyze non-stationary activation patterns and inter-neuronal dependencies in the motor and sensory cortices of two non-human primates during STN DBS. These features are enhanced after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes a consistent PD-like motor impairment, while high-frequency (HF) DBS (i.e., ≥100 Hz) strongly reduces the short-term patterns (period: 3–7 ms) both before and after MPTP treatment, and elicits a short-latency post-stimulus activation. Low-frequency DBS (i.e., ≤50 Hz), instead, has negligible effects on the non-stationary features. Finally, by using tools from the information theory [i.e., receiver operating characteristic (ROC) curve and information rate (IR)], we show that the predictive power of these models is dependent on the DBS settings, i.e., the probability of spiking of the cortical neurons (which is captured by the point process models) is significantly conditioned on the timely delivery of the DBS input. This dependency increases with the DBS frequency and is significantly larger for high- vs. low-frequency DBS. Overall, the selective suppression of non-stationary features and the increased modulation of the spike probability suggest that HF STN DBS enhances the neuronal activation in motor and sensory cortices, presumably because of reinforcement mechanisms, which perhaps involve the overlap between feedback antidromic and feed-forward orthodromic responses along the BG-thalamo-cortical loop.

Highlights

High-frequency (HF) Deep Brain Stimulation (DBS) of the basal ganglia (BG) is a clinically recognized treatment for movement disorders in Parkinson’s disease (PD), but its therapeutic mechanisms are still not fully understood (DeLong and Wichmann, 2007; Montgomery and Gale, 2008)
This study aims to (i) test the hypothesis in the non-human primate that the effects of subthalamic nucleus (STN) DBS on cortex vary with the stimulation frequency and involve reinforcement phenomena above 100 Hz; (ii) to determine whether the cortical response to DBS varies in normal vs. MPTP conditions; and (iii) to determine whether DBS affects the non-stationary dependencies between spike trains of neurons in small cortical ensembles
S1 cortex of non-human primates, (ii) the effects of DBS depend on the stimulation frequency and the disease conditions, and (iii) therapeutic 130 Hz STN DBS reduces short-term patterns and dependencies and evokes a short-latency phase-locked increment of the spiking activity, while non-therapeutic 50 Hz DBS reduces the burstiness of the spike trains (Gale, 2004)

Summary

Introduction

High-frequency (HF) Deep Brain Stimulation (DBS) of the basal ganglia (BG) is a clinically recognized treatment for movement disorders in Parkinson’s disease (PD), but its therapeutic mechanisms are still not fully understood (DeLong and Wichmann, 2007; Montgomery and Gale, 2008). Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated non-human primates showed that, in primary motor cortex (M1), Parkinsonism evokes bursting, synchronous oscillations and decreased specificity to movements, and may cause excessive synchronization between the BG and the cortex (Doudet et al, 1990; Watts and Mandir, 1992; Goldberg et al, 2002, 2004; Rivlin-Etzion et al, 2008, 2010). Excessive BG-cortex synchronization was confirmed in PD patients (Marsden et al, 2001; Fogelson et al, 2006; Lalo et al, 2008) Studies in both normal and 6-hydroxydopamine (OHDA)lesioned rodents (Li et al, 2007; Dejean et al, 2009; Gradinaru et al, 2009) reported that subthalamic nucleus (STN) DBS induces antidromic phase-locked cortical activation. DBS of the internal globus pallidus (GPi), instead, elicited phase-locked inhibition and decreased the discharge rate in the primary M1 cortex of a single MPTP non-human primate (Johnson et al, 2009)

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