Dysfunctional Limbic Circuitry Underlying Freezing of Gait in Parkinson's Disease

Abstract

Freezing of gait (FOG) is a poorly understood symptom affecting many patients with Parkinson's disease (PD). Despite growing evidence of a behavioral link between anxiety, attention and FOG in PD, no research to date has investigated the neural mechanisms that might explain this relationship. The present study therefore examined resting-state MRI functional connectivity between the amygdala, striatum and frontoparietal attentional control network in PD patients with (freezers: n = 19) and without FOG (non-freezers: n = 21) in the dopaminergic 'off' state. Functional connectivity was subsequently correlated with an objective measure of FOG severity and a subjective scale of affective disorder within each group. Connectivity between the right amygdala and right putamen was significantly increased in freezers compared to non-freezers (p < 0.01). Furthermore, freezers showed increased anti-coupling between the frontoparietal network and left amygdala (p = 0.011), but reduced anti-coupling between this network and the right putamen (p = 0.027) as compared to non-freezers. Key functional connections between the amygdala, putamen and frontoparietal network were significantly associated with FOG severity and a fear of falling. This study provides the first evidence that dysfunctional fronto-striato-limbic processes may underpin the link between anxiety and FOG in PD. It is proposed that freezers have heightened striato-limbic load and reduced top-down attentional control at rest, which when further challenged by the parallel processing demands of walking may precipitate FOG.

Keywords: Parkinson’s disease; amygdala; anxiety; functional MRI; gait disorders; putamen.

Figure 1:. Representation of the objective FOG severity measure (FOG-ratio)

Representation of the time and frequency analysis of the objective FOG severity measure (FOG-ratio). A) Time series of trunk and bilateral shin angular velocities during the turning task. B) Frequency analysis of the shin anteroposterior acceleration power spectral densities during the turning task. NOTE: PD-FOG=representative data from a relatively mobile PD patient without FOG; PD+FOG=representative data from a PD patient with severe FOG; FoG=Freezing of Gait.

Figure 2:. Regions of Interest (ROI)

Representation of the subcortical regions of interest (ROI) and the frontoparietal attention control network (Gordon et al., 2016) used in the current study.

Figure 3:. Representation of the rsFC differences found between PD+FOG and PD-FOG

Representation of the resting state functional connectivity (rsFC) differences found between Parkinson’s disease patient with freezing of gait (PD+FOG) and Parkinson’s disease patients without freezing of gait (PD-FOG). A) Amygdala - Striatum independent t-test results showing the average rsFC (Z-value) per group for the unilateral connections; B) Independent t-test results comparing the rsFC between the average time series of all 24 ROIs of the frontoparietal attentional control network (FPN) and the bilateral amygdala and putamen seeds showing the average rsFC (Z- value) per group; C) Visual representation of the results where coupling indicates increased correlations between BOLD time series while anti-coupling indicates increased negative correlations between BOLD time series. Put=Putamen (P); NAcc=Nucleus Accumbens (A); Caud=Caudate (C); Amyg=Amygdala (A). **Denotes statistical significance (p<0.05, FDR corrected); *Denotes statistical significance (p<0.05), but uncorrected; #Denotes a trend towards significance (p<0.1).