The effect of forced-exercise therapy for Parkinson's disease on motor cortex functional connectivity

Abstract

Parkinson's disease (PD) is a progressive neurologic disorder primarily characterized by an altered motor function. Lower extremity forced exercise (FE) has been shown to reduce motor symptoms in patients with PD. Recent functional magnetic resonance imaging (fMRI) studies have shown that FE and medication produce similar changes in brain activation patterns. Functional connectivity MRI (fcMRI) affords the ability to look at how strongly nodes of the motor circuit communicate with each other and can provide insight into the complementary effects of various therapies. Past work has demonstrated an abnormal motor connectivity in patients with PD compared to controls and subsequent normalization after treatment. Here we compare the effects of FE and medication using both resting and continuous visuomotor task fcMRI. Ten patients with mild to moderate PD completed three fMRI and fcMRI scanning sessions randomized under the following conditions: on PD medication, off PD medication, and FE+off medication. Blinded clinical ratings of motor function (a Unified Parkinson's Disease Rating Motor Scale-III exam) indicated that FE and medication resulted in 51% and 33% improvement in clinical ratings, respectively. In most nodes of the motor circuit, the observed changes in the functional connectivity produced by FE and medication were strongly positively correlated. These findings suggest that medication and FE likely use the same pathways to produce symptomatic relief in patients with PD. However, the connectivity changes, while consistent across therapy, were inconsistent in polarity for each patient. This finding may explain some past inconsistencies in connectivity changes after medication therapy.

FIG. 1.

Group averages in MNI space of activation to complex finger tapping task in an fMRI scan with (a) standard processing, (b) standard processing with a second-order motion correction applied before spatial smoothing, and (c) the image in (b), but with a lower threshold selected empirically to correspond to a threshold allowing the t score tails observed in (a). MNI, Montreal Neurologic Institute; fMRI, functional magnetic resonance imaging.

FIG. 2.

Histogram of maximum peak-to-peak motion parameters in scans 3 and 4.

FIG. 3.

Scatterplots of and linear correlation between Δf_c^FE and Δf_c^med for all patients included in an analysis (9 patients with const fcMRI, all 10 with resting fcMRI) for (a) M1 to SMA, (b) M1 to THAL, (c) M1 to PUT, (d) M1 to STN (not significant), (e) SMA to THAL, (f) SMA to PUT, (g) SMA to GP, and (h) SMA to STN. fcMRI, functional connectivity magnetic resonance imaging; SMA, supplementary motor area; THAL, thalamus; PUT, putamen; STN, subthalamic nucleus; GP, globus pallidus.