Deep brain stimulation of the pedunculopontine nucleus in Parkinson's disease. Preliminary experience at Oxford

Abstract

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) is a novel neurosurgical therapy developed to address symptoms of gait freezing and postural instability in Parkinson's disease and related disorders. Here, we summarize our non-human primate and neuroimaging research of relevance to our surgical targeting of the PPN. We also describe our clinical experience of PPN DBS with greatest motor improvements achieved by stimulation at low frequencies.

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

“…In light of these data, small experimental trials of low frequency PPN stimulation in humans were carried out. These studies have lead to variable results (Plaha and Gill, 2005;Stefani et al, 2007Stefani et al, , 2010Mazzone et al, 2007Mazzone et al, , 2008Pereira et al, 2008;Pierantozzi et al, 2008;Alessandro et al, 2010;Peppe et al, 2010;Rauch et al, 2010). In some patients, PPN DBS reduces gait and freezing problems unresponsive to drug and conventional stimulation approaches directed at subthalamic and pallidal targets, reduces falls and occasionally improves patients' state of vigilance and quality of sleep (Pereira et al, 2008;Ferraye et al, 2010).…”

“…These studies have lead to variable results (Plaha and Gill, 2005;Stefani et al, 2007Stefani et al, , 2010Mazzone et al, 2007Mazzone et al, , 2008Pereira et al, 2008;Pierantozzi et al, 2008;Alessandro et al, 2010;Peppe et al, 2010;Rauch et al, 2010). In some patients, PPN DBS reduces gait and freezing problems unresponsive to drug and conventional stimulation approaches directed at subthalamic and pallidal targets, reduces falls and occasionally improves patients' state of vigilance and quality of sleep (Pereira et al, 2008;Ferraye et al, 2010). The magnitude of the effects, the exact location of the stimulation electrode and best technique of implantation of DBS leads into this nucleus are still being debated (Aravamuthan et al, 2007(Aravamuthan et al, , 2008(Aravamuthan et al, , 2009Weinberger et al, 2008;Fu et al, 2009;Shimamoto et al, 2010).…”

Stereotactic implantation of deep brain stimulation electrodes: a review of technical systems, methods and emerging tools

“…Additional targets for deep brain stimulation are currently the subject of intensive research, and it can thus be expected that further types of neurological disturbances will become treatable with DBS. Examples of newer target areas include the pedunculopontine nucleus (PPN, for Parkinsonian manifestations such as impaired gait and balance) [98] the internal capsule (for obsessive-compulsive disorder) [21] and Brodmann area 25 (for depression) [82]. Other disorders that are under trial for DBS are epilepsy [116], Tourette syndrome [1], cluster headache [74] and schizophrenia [86].…”

The mode of action of electrical high frequency stimulation

“…Postural instability and gait disturbance are two very handicapping symptoms in Parkinson's disease, but can be markedly ameliorated by applying LFS to the pedunculopontine nucleus (PPN) [23,24]. In contrast to this, DBS of the cholinergic and glutamatergic PPN with a frequency of 100 Hz (approaching HFS) induced Parkinson-like akinesia and postural imbalance in non-human primates [25].…”

“…The described impairment may be attributed to a GABAergic inhibition of excitatory PPN neurons. This assumption is reinforced by the fact that in a monkey model of Parkinson's disease PPN lesioning also induced akinesia and postural instability [24]. This lesioning presumably means a withdrawal of PPN projection fibers; this would correspond with a HFS-induced local GABAergic inhibition of cholinergic and glutamatergic PPN neurons.…”