Imaging the lower limb network in Parkinson's disease

Abstract

Background: Despite the significant impact of lower limb symptoms on everyday life activities in Parkinson's disease (PD), knowledge of the neural correlates of lower limb deficits is limited.

Objective: We ran an fMRI study to investigate the neural correlates of lower limb movements in individuals with and without PD.

Methods: Participants included 24 PD and 21 older adults who were scanned while performing a precisely controlled isometric force generation task by dorsiflexing their ankle. A novel MRI-compatible ankle dorsiflexion device that limits head motion during motor tasks was used. The PD were tested on their more affected side, whereas the side in controls was randomized. Importantly, PD were tested in the off-state, following overnight withdrawal from antiparkinsonian medication.

Results: The foot task revealed extensive functional brain changes in PD compared to controls, with reduced fMRI signal during ankle dorsiflexion within the contralateral putamen and M1 foot area, and ipsilateral cerebellum. The activity of M1 foot area was negatively correlated with the severity of foot symptoms based on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III).

Conclusion: Overall, current findings provide new evidence of brain changes underlying motor symptoms in PD. Our results suggest that pathophysiology of lower limb symptoms in PD appears to involve both the cortico-basal ganglia and cortico-cerebellar motor circuits.

Keywords: BOLD; Force; Lower extremity; Parkinson’s disease; fMRI.

Fig. 1

Experimental setup and fMRI paradigm. (A) Custom-designed MRI compatible foot device placed on the MRI table along with pictures of the foot sensor used for the force production task. During the foot task, participants produced force by dorsiflexing the ankle. The tested side was the more affected side in PD and either the left or the right in controls (testing side was randomized in the control group; see Table 1). (B) fMRI paradigm. A block design was used. The foot task began with 30 s of rest, followed by 4 cycles consisting for 30 s force + 30 s rest. Each of the four force blocks contained 10 trials. During a trial, participants had to produce force for 2 s and relax for 1 s. A white bar represented their target and was set to be 15% of the effector/limb’s maximum voluntary contraction (MVC). Force generation was cued by a change in color of a force bar. When the force bar located at the bottom of the screen turned green, participants dorsiflexed their ankle to bring the force bar on top of a white bar (i.e., produce force). When the force bar located at the bottom of the screen turned red, participants relaxed their ankle to bring down the force bar to the bottom of the screen. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The figure illustrates the results of the whole-brain and cerebellum/brainstem-optimized analyses. Data represent the mean fMRI activity during the ankle dorsiflexion task for the PD and control groups. Brain data is overlaid on the MNI template. The color bars indicate the intensity of the fMRI results in t-values.

Fig. 3

(A) The figure depicts group differences in the fMRI activation during the ankle dorsiflexion task. The color scale uses warm colors for depicting brain regions where controls have greater activity than PD. Blue colors are used for any region where brain activity is greater in PD than in controls. Results are overlaid on the MNI template. Regions displaying activation had to meet a threshold of p < 0.001 and a cluster size of 54 µL, corresponding to a p < 0.05, corrected for multiple comparisons using the family-wise error (FWE) correction. (B) Correlation plots illustrating the relation in PD between PSC in the contralateral M1 foot area during the foot task and the severity of the disease expressed as the total MDS-UPDRS-III score and MDS-UPDRS-III subscore for the tested/more affected foot. Abbreviations: C = contralateral to the foot producing force; I = ipsilateral to the foot producing force; M1 = primary motor cortex; MDS-UPDRS-III = the motor section of the Movement Disorder Society Unified Parkinson's Disease Rating Scale; PSC = percent signal change. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

The figure depicts the normalized activation volume for each group, calculated for the main nodes of the motor circuit (i.e., basal ganglia, cortical motor regions and cerebellum). Values were obtained by masking the mean activity maps for each group derived from the voxel-wise statistical analyses with the following atlases: BGHAT, HMAT, and SUIT. The total number of active voxels was normalized by the size of the atlas. Results should be interpreted with caution due to the lack of a statistical analysis.