Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait

Abstract

Freezing of gait is one of the most debilitating symptoms in Parkinson's disease as it causes falls and reduces mobility and quality of life. The pedunculopontine nucleus is one of the major nuclei of the mesencephalic locomotor region and has neurons related to anticipatory postural adjustments preceding step initiation as well as to the step itself, thus it may be critical for coupling posture and gait to avoid freezing. Because freezing of gait and postural impairments have been related to frontal lesions and frontal dysfunction such as executive function, we hypothesized that freezing is associated with disrupted connectivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural connectivity of the pedunculopontine nucleus in patients with Parkinson's disease with freezing of gait, without freezing, and healthy age-matched controls. We also included behavioural tasks to gauge severity of freezing of gait, quantify gait metrics, and assess executive cognitive functions to determine whether between-group differences in executive dysfunction were related to pedunculopontine nucleus structural network connectivity. Using seed regions from the pedunculopontine nucleus, we were able to delineate white matter connections between the spinal cord, cerebellum, pedunculopontine nucleus, subcortical and frontal/prefrontal cortical regions. The current study is the first to demonstrate differences in structural connectivity of the identified locomotor pathway in patients with freezing of gait. We report reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus and multiple regions of the frontal cortex. Moreover, these structural differences were observed solely in the right hemisphere of patients with freezing of gait. Finally, we show that the more left hemisphere-lateralized the pedunculopontine nucleus tract volume, the poorer the performance on cognitive tasks requiring the initiation of appropriate actions and/or the inhibition of inappropriate actions, specifically within patients with freezing. These results support the notion that freezing of gait is strongly related to structural deficits in the right hemisphere's locomotor network involving prefrontal cortical areas involved in executive inhibition function.

Keywords: balance; diffusion tensor imaging; executive function; falls; inhibition; microstructure; white matter.

Figure 1

Location of region of interest for the pedunculopontine nucleus overlaid on MNI template in radiologic convention. (A) x = −7, y = −22, z = −22. pedunculopontine nucleus location mean (range) in MNI coordinates: ±7 (6–9), −32 (−30 to −35), −22 (−17 to −26). L = left; R = right.

Figure 2

Summed group images of fibre tracts passing through the right pedunculopontine nucleus region of interest in the coronal view (A) and the axial view (B). Data are displayed in MNI space on the 1 mm MNI template and are in radiologic convention. The colour bar describes the percentage of participants with overlap in the given region; warmer areas indicate regions of greater fibre tract overlap. FOG+ = patients with freezing of gait; FOG− = patients without freezing of gait; L = left; R = right.

Figure 3

Microstructural integrity and tract volume for locomotor network fibre tracts passing through the right and left pedunculopontine nucleus (PPN) regions of interest. No group or hemispheric differences were observed for microstructural integrity. Patients with freezing of gait (FOG+) had significantly reduced volume of fibre tracts solely in the right hemisphere compared to both healthy controls (HC) and patients without freezing of gait (FOG−). No differences were found between healthy control subjects and patients without freezing of gait. Data are mean ± SD, *P < 0.05, **P < 0.01. FA = fractional anisotropy; WM = white matter.

Figure 4

Axial view of right hemispheric pedunculopontine nucleus tracts observed in healthy control subjects and patients without freezing of gait, but not in patients with freezing of gait. Prominent areas include putamen, internal globus pallidum, thalamus, precentral gyrus, postcentral gyrus, superior frontal gyrus, middle frontal gyrus, supplementary motor area, pre-supplementary motor area, and cerebellar locomotor region. Data are displayed in MNI space on the 1 mm MNI template and are in radiologic convention. L = left; R = right.

Figure 5

(A) Significant group differences in laterality of fibre tract volume of locomotor network fibre tracts passing through the pedunculopontine nucleus (PPN). Pedunculopontine nucleus tract volume was significantly more left lateralized in patients with freezing of gait (FOG+) compared with patients without freezing of gait (FOG−) or healthy control subjects (HC). No differences were found between healthy control subjects and patients without freezing of gait. A value of zero would indicate equal pedunculopontine nucleus tract volume in the left and right hemisphere. Data are mean ± SD. (B) Linear regression between pedunculopontine nucleus tract laterality index and time to complete the Stroop conflict task as well as accuracy on the Flanker’s congruent task. Significant relationships exist solely for the group with freezing of gait, such that the more left-lateralized the pedunculopontine nucleus tract volume, the poorer the performance. Data are mean ± SD, *P < 0.05, **P < 0.01.