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.

Figure 1

Localization of stimulation locations (coloured dots) represented in Montreal Neurological Institute (MNI) space (sagittal and coronal views). The relative location/extent of the pedunculopontine nucleus has been outlined on the sagittal view, based on choline-acetyltransferase immunohistochemical (ChAT5) staining in the human. Coordinates were calculated in millimetres from midline (laterality), ventrodorsal distance (d) from floor of the fourth ventricle and rostro-caudal distance (h) from a pontomesencephalic line connecting the pontomesencephalic junction to the inferior colliculi caudal margin, as described previously (Ferraye et al., 2009). The mean (ranges) of these stimulation site coordinates were as follows: laterality 7.1 mm (4.6–9 mm), ventrodorsal distance (d) 5.8 mm (4.1–7.4 mm), rostro-caudal distance (h) −5.3 mm (−2.2 to −8.0 mm). In Montreal Neurological Institute space, the coordinates relative to the anterior commissure for the average stimulation location, was as follows; X = 7.1 mm, Y = −32 mm, Z = −22 mm. PM = ponto-mesencephalic line connecting the pontomesencephalic junction to the caudal end of the inferior colliculi; SC = superior colliculus; IC = inferior colliculus.

Figure 2

Gait analysis parameters (means ± SD) recorded when turning in a tight space, a task that precipitated visible gait freezing in PD-FOG patients but not in Parkinson’s disease controls or healthy controls. Results in PD-FOG patients are grouped according to stimulation condition: off stimulation, unilateral stimulation and bilateral stimulation. Unilateral stimulation results are the grand averages of the means of stimulating each side in each patient. (A) Turn task duration (s). (B) Turn task cadence (steps/min). Differences within the PD-FOG group are indicated by bridges: +P < 0.01, *P < 0.05. Compared to the off stimulation state, bilateral stimulation improved both parameters more than unilateral stimulation. Differences between groups were as follows: (i) turn task duration was longer for PD-FOG patients during all stimulation conditions than in either control group (P < 0.001); (ii) turn task cadence was smaller for PD-FOG patients when off stimulation and with unilateral stimulation than either control group (P < 0.05) but did not differ between PD-FOG patients when on bilateral stimulation and control groups (P = 0.882).