title: A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.
abstract: Gait freezing is an episodic arrest of locomotion due to an inability to take normal steps. Pedunculopontine nucleus stimulation is an emerging therapy proposed to improve gait freezing, even where refractory to medication. However, the efficacy and precise effects of pedunculopontine nucleus stimulation on Parkinsonian gait disturbance are not established. The clinical application of this new therapy is controversial and it is unknown if bilateral stimulation is more effective than unilateral. Here, in a double-blinded study using objective spatiotemporal gait analysis, we assessed the impact of unilateral and bilateral pedunculopontine nucleus stimulation on triggered episodes of gait freezing and on background deficits of unconstrained gait in Parkinson's disease. Under experimental conditions, while OFF medication, Parkinsonian patients with severe gait freezing implanted with pedunculopontine nucleus stimulators below the pontomesencephalic junction were assessed during three conditions; off stimulation, unilateral stimulation and bilateral stimulation. Results were compared to Parkinsonian patients without gait freezing matched for disease severity and healthy controls. Pedunculopontine nucleus stimulation improved objective measures of gait freezing, with bilateral stimulation more effective than unilateral. During unconstrained walking, Parkinsonian patients who experience gait freezing had reduced step length and increased step length variability compared to patients without gait freezing; however, these deficits were unchanged by pedunculopontine nucleus stimulation. Chronic pedunculopontine nucleus stimulation improved Freezing of Gait Questionnaire scores, reflecting a reduction of the freezing encountered in patients' usual environments and medication states. This study provides objective, double-blinded evidence that in a specific subgroup of Parkinsonian patients, stimulation of a caudal pedunculopontine nucleus region selectively improves gait freezing but not background deficits in step length. Bilateral stimulation was more effective than unilateral.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. wesley.thevathasan@nds.ox.ac.uk
authors.forename: Wesley
authors.initials: W
authors.lastname: Thevathasan
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cole
authors.forename: Cara L
authors.initials: CL
authors.lastname: Graepel
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hyam
authors.forename: Ned
authors.initials: N
authors.lastname: Jenkinson
authors.forename: John-Stuart
authors.initials: JS
authors.lastname: Brittain
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Coyne
authors.forename: Peter A
authors.initials: PA
authors.lastname: Silburn
authors.forename: Tipu Z
authors.initials: TZ
authors.lastname: Aziz
authors.forename: Graham
authors.initials: G
authors.lastname: Kerr
authors.forename: Peter
authors.initials: P
authors.lastname: Brown
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D016022:Case-Control Studies; D046690:Deep Brain Stimulation / Q000379:methods*; D004566:Electrodes; D005260:Female; D007839:Functional Laterality; D020233:Gait Disorders, Neurologic / Q000209:etiology* / Q000628:therapy*; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D010300:Parkinson Disease / Q000150:complications*; D045042:Pedunculopontine Tegmental Nucleus / Q000502:physiology*; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome