Short CommunicationEffect of globus pallidus internus stimulation on neuronal activity in the pedunculopontine tegmental nucleus in the primate model of Parkinson's disease
Highlights
► We examined the effect of GPi DBS on PPN neuronal activity in the MPTP monkey. ► Single neuron activity was recorded from the PPN before, during, and after GPi DBS. ► Therapeutic GPi DBS reduced the mean discharge rate of PPN neurons. ► Therapeutic GPi DBS increased low frequency oscillatory neuronal activity.
Introduction
Deep brain stimulation (DBS) has revolutionized the treatment of Parkinson's disease (PD) and renewed exploration of surgical therapy for a wide range of neurological disorders (Constantoyannis et al., 2004, Greenberg et al., 2008, Hariz et al., 2002, Houeto et al., 2005, Magarinos-Ascone et al., 2008, Witjas et al., 2005, Wyckhuys et al., 2009). Chronic, high-frequency stimulation of the internal segment of the globus pallidus (GPi) is an effective therapy for tremor, rigidity, and bradykinesia as well as dopamine responsive gait, balance and freezing disorders. For a subset of patients, particularly those in the advanced stages of the disease, difficulties with gait, balance and freezing may be unresponsive to GPi or subthalamic nucleus (STN) DBS as well as to levodopa replacement therapy. This has led some to hypothesize that the pathophysiological basis underlying these axial motor symptoms involves anatomical pathways outside of the traditional pallido-thalamo-cortical neuronal circuitry (Allert et al., 2001, Bonnet et al., 1987, Faist et al., 2001, Ferrarin et al., 2005, Liu et al., 2005, Lubik et al., 2006, Tagliati et al., 2008), including brainstem areas like the peduncupontine tegmental nucleus (PPN). The PPN receives input from both the basal ganglia and the spinal cord and its cholinergic and glutamatergic neurons project, in turn, to widespread basal ganglia, thalamic, brainstem and spinal cord targets. It is known to play a role in the initiation, maintenance and modulation of gait and postural stability (Lee et al., 2000), which has led a number of researchers to explore the PPN as a possible therapeutic target for patients with medically refractory gait and postural abnormalities (Jenkinson et al., 2004, Mazzone et al., 2005, Nandi et al., 2002, Pereira et al., 2008, Plaha and Gill, 2005, Stefani et al., 2007). To date, the results of those preliminary studies have been mixed, as some have reported significant improvement in response to low frequency PPN DBS (Jenkinson et al., 2004, Mazzone et al., 2005, Nandi et al., 2002, Pereira et al., 2008, Plaha and Gill, 2005) while others have failed to observe benefit (Stefani et al., 2007).
Given the current interest in the PPN as a therapeutic target and its proposed mechanism of action, i.e., activation of PPN output, an understanding of the effect of GPi and STN DBS on PPN activity is critically important. In this study, we investigated the effect of therapeutic GPi DBS on PPN neuronal activity in a rhesus monkey rendered parkinsonian using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). By examining the effect of GPi DBS on PPN neuronal activity, we may better understand why GPi DBS has limited effect on medically refractory gait and postural abnormalities and devise alternative approaches and targets for its treatment.
Section snippets
Methods
All experimental procedures were approved by the Institutional Animal Care and Use Committee and complied with United States Public Health Service policy on the humane care and use of laboratory animals. Surgical procedures were performed in aseptic conditions using isoflurane anesthesia. A single, female monkey (Macaca mulatta, 5 kg, 9 years) was used for this study.
Behavioral changes
Optimal therapeutic parameters for GPi DBS at a pre-set pulse rate of 135 Hz were identified as using contacts 2 and 1 as the cathode and anode, respectively, with a pulse amplitude of 6.0 V. Stimulation at these settings was associated with improvements across all activity metrics applied. A significant improvement in spontaneous cage behavior activity was marked by an increase in movement of the affected upper (93 s to 214 s per 20 min) and lower extremity (73 s to 161 s/20 min) as shown in Fig. 1A.
Discussion
In this study, we examined the effect of high-frequency stimulation of the GPi on PPN neuronal activity in a single non-human primate made moderately parkinsonian with the neurotoxin MPTP. We observed a reduction in the mean discharge rate and burst activity of the majority of PPN neurons during GPi DBS. The inhibition of PPN observed in our study is consistent with the activation of GABAergic output of the GPi during DBS as previously reported by our group (Hashimoto et al., 2003, Vitek et
Conclusion
GPi DBS suppressed neuronal activity in the PPN in the MPTP-treated primate. This is consistent with activation of GABAergic projections from the GPi to the PPN and previous observations that stimulation increases output from the stimulated structure. This occurred coincident with improvement in rigidity and bradykinesia. Given the reported lack of improvement in MRGPA with GPi DBS, the present study together with previous reports of improvement in MRGPA during low frequency stimulation in PPN
Acknowledgment
This work was supported by the National Institutes of Health Grant NS037019 and NS068231.
References (41)
- et al.
Chronic implantation of deep brain stimulation leads in animal models of neurological disorders
J. Neurosci. Methods
(2005) - et al.
A template subtraction method for stimulus artifact removal in high-frequency deep brain stimulation
J. Neurosci. Methods
(2002) - et al.
Quantitative assessments of the effect of bilateral subthalamic stimulation on multiple aspects of sensorimotor function for patients with Parkinson's disease
Parkinsonism Relat. Disord.
(2005) - et al.
Deep brain stimulation in the globus pallidus to treat dystonia: electrophysiological characteristics and 2 years' follow-up in 10 patients
Neuroscience
(2008) - et al.
Deep brain stimulation of the pedunculopontine region in the normal non-human primate
J. Clin. Neurosci.
(2002) - et al.
Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinson's disease
Mov. Disord.
(2001) - et al.
Does long-term aggravation of Parkinson's disease result from nondopaminergic lesions?
Neurology
(1987) Bad oscillations in Parkinson's disease
J. Neural Transm.
(2006)- et al.
Tremor induced by thalamic deep brain stimulation in patients with complex regional facial pain
Mov. Disord.
(2004) - et al.
Effect of bilateral subthalamic nucleus stimulation on gait in Parkinson's disease
Brain
(2001)
Effects of bilateral subthalamic stimulation on gait kinematics and kinetics in Parkinson's disease
Exp. Brain Res.
Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive–compulsive disorder: worldwide experience
Mol. Psychiatry
Impact of thalamic deep brain stimulation on disability and health-related quality of life in patients with essential tremor
J. Neurol. Neurosurg. Psychiatry
Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons
J. Neurosci.
Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD
Neurology
Tourette's syndrome and deep brain stimulation
J. Neurol. Neurosurg. Psychiatry
Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease
Ann. Neurol.
Medium Frequency Subthalamic Stimulation for Axial Symptoms in Advanced Parkinsons Disease
Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease
Mov. Disord.
Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey
Neuroreport
Cited by (35)
Dynamical role of pedunculopntine nucleus stimulation on controlling Parkinson's disease
2019, Physica A: Statistical Mechanics and its ApplicationsCitation Excerpt :PPN receives projections from STN, GPi, substantia nigra pars reticulate (SNr), cortex and spinal cord. STN sends signal to PPN, which has been shown to be glutamatergic in the rat [14,16], while GABAergic inputs to PPN from GPi and SNr [16–18]. In addition, PPN sends a mixed cholinergic and glutamatergic projection to SNr, substantia nigra pars compacta (SNc) [19–21] and GPi [2,14,22].
Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease
2017, Brain StimulationCitation Excerpt :Multiple other studies, however, have reported increased cGMP levels in the GPi [28] [29] [30] and in the SNr [30] during STN DBS suggesting increased levels of synaptic/metabolic activity consistent with activation of output from the stimulated structure. Regardless of whether one supports the inhibition or activation hypothesis, the far-reaching effect of DBS on other structures in the circuit is supported by a number of studies demonstrating alterations in cortical activity with STN [31] [32] or GPi DBS [33] as well as previous modeling [34,35] and animal studies recording from multiple structures in the circuit [9,24] [36–38]. Changes in extracellular concentrations of striatal GABA and glutamate during STN stimulation lend further support to the varied and complex changes that occur during DBS [39,40].
Low-frequency deep brain stimulation for movement disorders
2016, Parkinsonism and Related DisordersCitation Excerpt :It has been proposed that this frequency plateau in PPN cells explains the requirement to stimulate at low frequencies in order to induce locomotion [80]. Furthermore, the PPN seems to be overinhibited in PD by increased GABA-ergic input from the GPi [81,82]. This inhibition would be overcome by DBS.