Effect of dopamine on limbic network connectivity at rest in Parkinson's disease patients with freezing of gait

Abstract

Background: Freezing of gait (FOG) in Parkinson's disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine "OFF" state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear.

Objective: To evaluate how dopamine therapy alters resting state functional connectivity (rsFC) of the fronto-striato-limbic circuitry in PD freezers, and whether the degree of connectivity change is related to freezing severity and anxiety.

Methods: Twenty-three PD FOG patients underwent MRI at rest (rsfMRI) in their clinically defined "OFF" and "ON" dopaminergic medication states. A seed-to-seed based analysis was performed between a priori defined limbic circuitry ROIs. Functional connectivity was compared between OFF and ON states. A secondary correlation analyses evaluated the relationship between Hospital Anxiety and Depression Scale (HADS)-Anxiety) and FOG Questionnaire with changes in rsFC from OFF to ON.

Results: PD freezers' OFF compared to ON showed increased functional coupling between the right hippocampus and right caudate nucleus, and between the left putamen and left posterior parietal cortex (PPC). A negative association was found between HADS-Anxiety and the rsFC change from OFF to ON between the left amygdala and left prefrontal cortex, and left putamen and left PPC.

Conclusion: These findings suggest that dopaminergic medication partially modulates the frontoparietal-limbic-striatal circuitry in PD freezers, and that the influence of medication on the amygdala, may be related to clinical anxiety in freezer.

Keywords: Parkinson’s disease; amygdala; anxiety; emotion; fMRI; freezing of gait; levodopa; resting state; resting-state functional connectivity; striatum.

Figure 1

rsFC results in freezers OFF and ON dopaminergic medication. (a) ROI to ROI functional connectivity t-statistic connectivity graph and matrices of 14 ROIs averaged across all subjects between each pair of ROIs, in the OFF and ON medication states, respectively. The ROI to ROI connectivity lies on a spectrum between red and blue, where red indicates a positive rsFC and blue indicates a negative rsFC. The varying shades of colours from red to blue represents the strength of connectivity, where a darker shade indicates a stronger connectivity. (b) RSFC Fisher-Z correlation coefficient values in the OFF and ON medication states between selected ROI to ROI connectivity. Standard error bars included. Legend: (P) = Putamen; (C) = Caudate; (N) = Nucleus Accumben; (A) = Amygdala; (H) = Hippo = Hippocampus; (FPN) = Fronto-parietal Attentional Network; (FPN PPC) = FPN posterior parietal cortex. *Denotes statistical significance (p < 0.05, FDR Uncorrected); # Denotes a trend towards significance (p < 0.1). (c) This figure depicts a visual representation of the results. Darker colours represent a stronger connectivity and lighter colours represent a weaker connectivity.

Figure 2

Correlation scatterplot that showed a negative correlation between HADS-Anxiety and the rsFC difference comparing OFF and ON medication states (OFF–ON) between the left amygdala and left LPFC. Findings indicated that higher baseline anxiety levels were associated with greater connectivity between these regions in the ON compared to the OFF medication state, whereas lower anxiety levels were associated with reduced connectivity between these regions in the ON compared to the OFF medication state.

Figure 3

Correlation scatterplot that showed a positive correlation between HADS-Anxiety and the rsFC difference comparing OFF and ON medication states (OFF–ON) between the left putamen and left PPC. Findings indicated that higher baseline anxiety levels were associated with greater connectivity between these regions in the OFF compared to the ON medication state, whereas lower anxiety levels were associated with increased connectivity between these regions in the ON compared to the OFF-medication state.