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

Dione Y L Quek; Natasha Taylor; Moran Gilat; Simon J G Lewis; Kaylena A Ehgoetz Martens

doi:10.1515/tnsci-2022-0336

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

Transl Neurosci. 2024 May 2;15(1):20220336. doi: 10.1515/tnsci-2022-0336. eCollection 2024 Jan 1.

Authors

Dione Y L Quek¹, Natasha Taylor¹, Moran Gilat², Simon J G Lewis¹, Kaylena A Ehgoetz Martens^{1

3}

Affiliations

¹ Parkinson's Disease Research Clinic, Brain and Mind Centre, University of Sydney, Sydney, Australia.
² Neurorehabilitation Research Group (eNRGy), Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium.
³ Department of Kinesiology and Health Sciences, University of Waterloo, 200 University Avenue West, Waterloo ON, N2L3G1 Canada.

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.