Identifying the neural correlates of doorway freezing in Parkinson's disease

Abstract

Freezing of gait (FOG) in Parkinson's disease (PD) is frequently triggered upon passing through narrow spaces such as doorways. However, despite being common the neural mechanisms underlying this phenomenon are poorly understood. In our study, 19 patients who routinely experience FOG performed a previously validated virtual reality (VR) gait paradigm where they used foot‐pedals to navigate a series of doorways. Patients underwent testing randomised between both their “ON” and “OFF” medication states. Task performance in conjunction with blood oxygenation level dependent (BOLD) signal changes between “ON” and “OFF” states were compared within each patient. Specifically, as they passed through a doorway in the VR environment patients demonstrated significantly longer “footstep” latencies in the OFF state compared to the ON state. As seen clinically in FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. Functional magnetic resonance imaging revealed that footstep prolongation on passing through doorways was associated with selective hypoactivation in the presupplementary motor area (pSMA) bilaterally. Task‐based functional connectivity analyses revealed that increased latency in response to doorways was inversely correlated with the degree of functional connectivity between the pSMA and the subthalamic nucleus (STN) across both hemispheres. Furthermore, increased frequency of prolonged footstep latency was associated with increased connectivity between the bilateral STN. These findings suggest that the effect of environmental cues on triggering FOG reflects a degree of impaired processing within the pSMA and disrupted signalling between the pSMA and STN, thus implicating the “hyperdirect” pathway in the generation of this phenomenon.

Freezing of gait in Parkinson’s disease reflects a sudden derangement of locomotor network dynamics

“…The origin of these dysfunctional dynamics is unclear. One possibility is that the deficient cortical-subcortical communication in gait freezing relies on a defective engagement of the SMA (Hanakawa et al , 1999; Iseki et al , 2010; Tard et al , 2015; Matar et al , 2018, 2019) in the context of basal ganglia pathology (de Hemptinne et al , 2013; Brittain and Brown, 2014; Lewis and Shine, 2016). Indeed, the cortical-subthalamic decoupling was limited to the hemisphere with greater dopaminergic denervation in a context of unbalanced dopaminergic loss between the two hemispheres.…”

“…and leading to unsuccessful attempts at forward stepping (Schlenstedt et al , 2018). Recent findings with functional MRI have revealed that doorway-provoked gait freezing (in virtual reality) was associated with selective hypoactivation of the (pre)SMA (Matar et al , 2018, 2019). In this study, the authors also showed a cortical-subthalamic decoupling during gait freezing thus further supporting our real-life results (Matar et al , 2018, 2019).…”

Cortical and subcortical functional specificity associated with response inhibition.

“…Aron et al, 2007;Aron and Poldrack, 2006;Jahfari et al, 2011;Rae et al, 2015). Further, efficiency of inhibitory control is dependent on the strength of fronto-basal ganglia connectivity (Chavan et al, 2017;Forstmann et al, 2012;Jahfari et al, 2012;Matar et al, 2019). Motor output through the thalamus (THAL) is thought to be under the direction of signals originating from frontal regions via three pathways through the basal ganglia; the direct, indirect and hyperdirect pathways (see Fig.…”

Virtual visual cues : vice or virtue?

“…A complicating factor is that a validated paradigm to study visually cued lower limb movement (as a proxy for gait) in a neuroimaging study is not yet available. Unfortunately, our attempt to extend an established virtual environment paradigm (54,55,57,(71)(72)(73)(74)(75) by incorporating visual cues did not result in a validated paradigm for future use in neuroimaging studies and behavioural studies on visual cueing in persons with PD and FOG (Chapter 10). As discussed elaborately in the Discussion section of Chapter 10, the visual cues in the virtual environment apparently 'did not have what it takes' to improve movement control.…”

“…However, improvements to the paradigm, such as strengthening the coupling between foot movements and the view in the virtual environment, could render the paradigm better suited for the purpose of studying the neurophysiology of cueing. Considering the value that the virtual environment paradigm has had in the study of the pathophysiology of FOG (54,55,57,(71)(72)(73)(74)(75), this paradigm, if adjusted, does hold potential to study the neurophysiological grounds of visual cueing.…”