Lesions causing freezing of gait localize to a cerebellar functional network

Abstract

Objective: Freezing of gait is a disabling symptom in Parkinson disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation.

Methods: Fourteen cases of lesion-induced freezing of gait were identified from the literature, and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion-induced disorders.

Results: Lesion location was heterogeneous, and no single region could be considered necessary for symptom generation. However, > 90% (13 of 14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis).

Interpretation: Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson disease patients, advancing our understanding of the brain regions involved in freezing of gait. ANN NEUROL 2017;81:129-141.

Figure 1

A) Lesion location for 14 cases of lesion-induced FOG, manually traced onto a reference brain (MNI152 template). All lesions were traced true to their laterality, right/left orientation for each lesion as shown on the upper left cross-section. B) Lesion network mapping technique. Each lesion location (left) was used as a seed region to generate a functional connectivity map based on resting state fMRI data from healthy controls (middle). The 14 functional connectivity maps were then overlapped to identify brain regions functionally connected to the greatest number of lesion locations (right).

Figure 2

Lesion network mapping results. The vast majority (> 90%) of lesion locations resulting in FOG were positively correlated to sites in the cerebellum (A), thalamus (B) and anti-correlated to sites in the subcallosal cingulate (C). Functional connectivity maps from lesions causing FOG were compared with those causing other movement disorders (asterixis and hemichorea-hemiballismus) using two statistical tests: voxel-wise Leibermeister test (D–F) and unpaired t test (G–I). FOG lesion network overlap sites in the cerebellum, thalamus and subcallosal cingulate (see panels A-C) are outlined in light grey (green in the online version of the figure) for reference. Statistical comparison maps were masked to the cerebellum (D, G), thalamus (E, H) and subcallosal cingulate (F, I), using Harvard-Oxford structural atlases. Connectivity to the dorsal medial cerebellum, but not the thalamus or subcallosal cingulate, is specific to lesions causing FOG.

Figure 3

Lesion network mapping results in the cerebellum are robust to several different analysis approaches. Lesion networks derived from FOG lesions are compared to those from asterixis lesions using two statistical tests: unpaired t test (A) or Leibermeister test (B) and to hemichorea-hemiballismus lesions using an unpaired t test (C) or Leibermeister test (D). Lesion network overlap persists in the same location when the inclusion criteria are restricted to cases of acute stroke (E) and remains specific when compared to other movement disorders (asterixis and hemichorea) (F). All images are masked to the cerebellum. The original FOG network overlap site in the cerebellum (see Figure 2A) is outlined in light grey (green in the online version of the figure) for reference.

Figure 4

Lesions causing FOG are more connected to cerebellar locomotion regions (CLR) than lesions causing other movement disorders. (A) Mean correlation between lesions causing different movement disorders and one of two putative CLR sites. Topographical display of the FOG lesion network overlap map (B) and voxel-wise t test map comparing FOG to hemichorea-hemiballismus and asterixis (C) are overlaid on two 6mm ROIs centered at the CLR site as outlined by Jahn et al (dark grey, blue in the online version of the figure) and Jaeger et al. (light grey, green in the online version of the figure). T- test map was placed in front (B) or behind (C) the CLR ROIs for display purposes. ***P<0.001, **P<0.005, *P<0.05.

Figure 5

Resting-state functional connectivity with the FOG network overlap site in the cerebellum. The map is displayed on the cortical surface using CARET (A) highlighting the bilateral leg area of the primary motor cortex. The same map is displayed on an MNI template brain (B) highlighting subcortical network nodes. Superimposed on the network map in (B) are lesions causing FOG (in dark grey and circled in light grey, blue and circled in green in the online version of the figure).