The Contribution of Noradrenergic Activity to Anxiety‐Induced Freezing of Gait

Abstract

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

Modulating arousal to overcome gait impairments in Parkinson’s disease: how the noradrenergic system may act as a double-edged sword

“…Overactivation of the locus coeruleus (i.e., supraoptimal arousal), on the other hand, may lead to a situation that allows for an element of increased, dysfunctional ‘cross-talk’ between competing inputs of these complementary networks [ 51 ]. In PD specifically, this has been associated with detrimental effects on motor function, particularly the occurrence of anxiety-induced freezing of gait [ 52 – 54 ]. Unfortunately, the ability to adaptively employ the locus coeruleus to optimally modulate the interaction of compensatory networks may be affected by the profound degeneration of the nucleus in PD, and this is compounded by dysfunction of cortical regions in charge of regulating arousal.…”

Impaired structural and reserved functional topological organizations of brain networks in Parkinson’s disease with freezing of gait

“…Clinical studies have disclosed that anxiety and depression are common non-motor features in PD-FOG that crucially contribute to FOG occurrence (61). It is suggested that emotional loading could detract attentional resources in PD-FOG, in turn leading to abrupt gait dysfunction (4,62). Thus, to reduce the potential confounding effects of emotion, we added the HAMA and HAMD-24 scores as covariates in imaging analyses.…”

Noradrenaline and Movement Initiation Disorders in Parkinson’s Disease: A Pharmacological Functional MRI Study with Clonidine

“…It has become increasingly apparent that the neuropathological changes of PD extend well beyond the nigrostriatal system, pointing especially to the early involvement of the LC in the neurodegenerative process underlying the disease [ 72 , 73 ]. Of interest, the NA system is thought to be involved in the pathophysiology of gait disorders in PD, such as freezing of gait which can be viewed as a failure to initiate movement [ 74 , 75 , 76 ].…”