The Contribution of Noradrenergic Activity to Anxiety-Induced Freezing of Gait.

BACKGROUND: Freezing of gait is a complex paroxysmal phenomenon that is associated with a variety of sensorimotor, cognitive and affective deficits, and significantly impacts quality of life in patients with Parkinson's disease (PD). Despite a growing body of evidence that suggests anxiety may be a crucial contributor to freezing of gait, no research study to date has investigated neural underpinnings of anxiety-induced freezing of gait. OBJECTIVE: Here, we aimed to investigate how anxiety-inducing contexts might "set the stage for freezing," through the ascending arousal system, by examining an anxiety-inducing virtual reality gait paradigm inside functional magnetic resonance imaging (fMRI). METHODS: We used a virtual reality gait paradigm that has been validated to elicit anxiety by having participants navigate a virtual plank, while simultaneously collecting task-based fMRI from individuals with idiopathic PD with confirmed freezing of gait. RESULTS: First, we established that the threatening condition provoked more freezing when compared to the non-threatening condition. By using a dynamic connectivity analysis, we identified patterns of increased "cross-talk" within and between motor, limbic, and cognitive networks in the threatening conditions. We established that the threatening condition was associated with heightened network integration. We confirmed the sympathetic nature of this phenomenon by demonstrating an increase in pupil dilation during the anxiety-inducing condition of the virtual reality gait paradigm in a secondary experiment. CONCLUSIONS: In conclusion, our findings represent a neurobiological mechanistic pathway through which heightened sympathetic arousal related to anxiety could foster increased "cross-talk" between distributed cortical networks that ultimately manifest as paroxysmal episodes of freezing of gait. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

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.

The influence of visual feedback on alleviating freezing of gait in Parkinson's disease is reduced by anxiety.

BACKGROUND: Previous research has established that anxiety is associated with freezing of gait (FOG) in Parkinson's disease (PD). Although providing body-related visual feedback has been previously suggested to improve FOG, it remains unclear whether anxiety-induced FOG might be improved. RESEARCH QUESTION: The current study aimed to evaluate whether body-related visual feedback (VF) improves FOG consistently across low and high threat conditions. METHODS: Sixteen PD patients with FOG were instructed to walk across a plank in a virtual environment that was either located on the ground (low threat) or elevated above a deep pit (high threat). Additionally, visual feedback (VF) was either provided (+) or omitted (-) using an avatar that was synchronised in real-time with the participants movements. RESULTS: revealed that in the low threat condition (i.e., ground), %FOG was significantly reduced when VF was provided (VF+) compared to when VF was absent (VF-). In contrast, during the elevated high threat condition, there were no differences in %FOG regardless of whether VF was provided or not. SIGNIFICANCE: These findings confirm that although VF can aid in the reduction of FOG, anxiety may interfere with freezers' ability to use sensory feedback to improve FOG and hence, in high threat conditions, VF was unable to aid in the reduction of FOG. Future studies should direct efforts towards the treatment of anxiety to determine whether better management of anxiety may improve FOG.

Heart Rate Changes Prior to Freezing of Gait Episodes Are Related to Anxiety.

BACKGROUND: Freezing of gait (FOG) in Parkinson's disease (PD) has been shown to be more frequent in stressful situations, implicating anxiety. Heart rate (HR) has been shown to increase prior to a FOG episode supporting the notion that elevated stress levels may trigger FOG. However, no studies to date have investigated whether elevated HR precedes all subtypes of FOG or only those episodes that are driven by anxiety. OBJECTIVE: The present study sought to investigate whether 1) HR increases prior to FOG episodes in nonspecific environments (Experiment 1), and if 2) HR increases prior to FOG when provoked in high but not low threat environments using a virtual reality paradigm (Experiment 2). METHODS: In Experiment 1, 10 of 19 participants with PD and FOG (PD + FOG) experienced FOG during a series of walking trials. In Experiment 2, 12 of 23 participants with PD + FOG experienced FOG while walking across an elevated and ground level narrow plank in virtual reality. HR was collected throughout the duration of both experiments, while FOG was quantified by experts using video review and tagging. RESULTS: HR significantly increased 2-3 seconds prior to a FOG episode during Experiment 1. In Experiment 2, HR significantly increased 4-6 seconds prior to a FOG episode, specifically while navigating the elevated plank. However, there were no significant increases in HR prior to FOG episodes when participants navigated the ground plank. CONCLUSION: This study extends previous work further demonstrating that increases in HR prior to FOG episodes appear linked to elevated anxiety levels.

Validating a Seated Virtual Reality Threat Paradigm for Inducing Anxiety and Freezing of Gait in Parkinson's Disease.

BACKGROUND: Although prior research has established that freezing of gait (FOG) in Parkinson's disease (PD) is associated with anxiety, only one study to date has directly manipulated anxiety levels to induce FOG. OBJECTIVE: The current study aimed to replicate these previous findings and evaluate whether a seated version of a 'threat' virtual reality (VR) paradigm could induce anxiety and provoke FOG. METHODS: Twenty-four PD patients with FOG were assessed across various threat conditions in both a walking VR paradigm (Experiment 1) and a seated VR paradigm (Experiment 2). Both paradigms manipulated the height (i.e., elevated vs ground) and width (wide vs narrow) of the planks participants were instructed to walk across. RESULTS: Across both experiments, the Elevated + Narrow condition provoked significantly greater number of freezing episodes compared to all other conditions. Higher levels of self-reported anxiety were reported during the Elevated+Narrow condition compared to all other conditions in Experiment 1, and compared to the Ground condition in Experiment 2. CONCLUSION: These findings confirm that anxiety contributes to FOG and validates the use of a seated VR threat paradigm for provoking anxiety-related freezing. This enables future studies to combine this paradigm with functional MRI to explore the neural correlates underlying the role of anxiety in FOG.