Elsevier

Experimental Neurology

Volume 233, Issue 1, January 2012, Pages 575-580
Experimental Neurology

Short Communication
Effect of globus pallidus internus stimulation on neuronal activity in the pedunculopontine tegmental nucleus in the primate model of Parkinson's disease

https://doi.org/10.1016/j.expneurol.2011.07.007Get rights and content

Abstract

The pedunculopontine tegmental nucleus (PPN) is being explored as a site for deep brain stimulation (DBS) for the treatment of patients with medically refractory gait and postural abnormalities (MRGPA) associated with Parkinson's disease (PD). The PPN is involved in initiation and modulation of gait and other stereotyped motor behaviors and is inter-connected with the pallido-thalamo-cortical circuit. Internal segment of the globus pallidus (GPi) DBS is effective at treating the motor signs associated with PD, however its impact on MRGPA is limited and its effect on PPN neuronal activity is unknown. The current work characterizes the effect of therapeutically-effective GPi DBS on PPN neuronal activity in a single rhesus monkey made parkinsonian using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A scaled-down, quadripolar DBS lead was implanted into sensorimotor GPi under electrophysiological and stereotactic guidance. Single-neuron activity was recorded from PPN before, during and after DBS. GPi DBS reduced the mean discharge rate of PPN neurons from 16.8 Hz to 12.8 Hz, with 30 (66.7%) neurons showing a decreased mean rate, 3 (6.7%) increased and 12 (26.7%) unchanged. Consistent with known GABAergic projections from GPi to PPN, and with previous observations that stimulation increases output from the stimulated structure, GPi DBS suppressed activity in the PPN. The present observations, together with previous reports of improvement in MRGPA during low frequency stimulation in PPN, suggest that activation of PPN output may be required to improve MRGPA and may account for the lack of improvement in MRGPA typically observed with GPi or subthalamic nucleus (STN) DBS.

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)

  • M. Ferrarin et al.

    Effects of bilateral subthalamic stimulation on gait kinematics and kinetics in Parkinson's disease

    Exp. Brain Res.

    (2005)
  • B.D. Greenberg et al.

    Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive–compulsive disorder: worldwide experience

    Mol. Psychiatry

    (2008)
  • G.M. Hariz et al.

    Impact of thalamic deep brain stimulation on disability and health-related quality of life in patients with essential tremor

    J. Neurol. Neurosurg. Psychiatry

    (2002)
  • T. Hashimoto et al.

    Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons

    J. Neurosci.

    (2003)
  • T. Hershey et al.

    Cortical and subcortical blood flow effects of subthalamic nucleus stimulation in PD

    Neurology

    (2003)
  • J.L. Houeto et al.

    Tourette's syndrome and deep brain stimulation

    J. Neurol. Neurosurg. Psychiatry

    (2005)
  • W.D. Hutchison et al.

    Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease

    Ann. Neurol.

    (1998)
  • M.G. Jabre et al.

    Medium Frequency Subthalamic Stimulation for Axial Symptoms in Advanced Parkinsons Disease

    (2008)
  • R. Jech et al.

    Functional magnetic resonance imaging during deep brain stimulation: a pilot study in four patients with Parkinson's disease

    Mov. Disord.

    (2001)
  • N. Jenkinson et al.

    Pedunculopontine nucleus stimulation improves akinesia in a Parkinsonian monkey

    Neuroreport

    (2004)
  • Cited by (35)

    • Dynamical role of pedunculopntine nucleus stimulation on controlling Parkinson's disease

      2019, Physica A: Statistical Mechanics and its Applications
      Citation 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 Stimulation
      Citation 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 Disorders
      Citation 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.

    View all citing articles on Scopus
    View full text