Aberrant functional connectivity in patients with Parkinson’s disease and freezing of gait: a within- and between-network analysis

IntroductionFreezing of gait (FOG) in Parkinson’s disease (PD) is a disabling symptom of advanced PD and is frequently triggered upon passing through narrow spaces such as doorways.1 Despite being common, the mechanisms underlying this phenomenon are poorly understood. We have previously shown that increased footstep latency in a virtual reality (VR) environment is a surrogate measure of FOG.2 In this study we aimed to model doorway freezing utilising the VR paradigm in conjunction with functional magnetic resonance imaging (fMRI) to determine the neural correlates of this phenomenon.MethodsIn our study, nineteen patients who routinely experience FOG performed a previously validated VR gait paradigm3 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 signal changes were compared within each patient.ResultsWe were able to reproduce the finding that patients in the OFF state demonstrated significantly longer ‘footstep’ latencies as they passed through a doorway in the VR environment compared to the ON state. As seen clinically with FOG this locomotive delay was primarily triggered by narrow doorways rather than wide doorways. fMRI analysis revealed that doorway-provoked footstep delay was associated with selective hypoactivation in the pre-supplementary motor area (pSMA) bilaterally. Task-based functional connectivity analyses showed that this delay 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.ConclusionThese 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.References. Giladi N, Treves TA, Simon ES, Shabtai H, Orlov Y, Kandinov B, Paleacu D, Korczyn AD. Freezing of gait in patients with advanced Parkinson’s disease. J Neural Transm (Vienna)2001;108:53–61.. Matar E, Shine JM, Naismith SL, Lewis SJ.Virtual realitywalking and dopamine: opening new doorways to understanding freezing of gait in Parkinson’s disease. J Neurol Sci 2014;344:182–5.. Shine JM, Matar E, Bolitho SJ, Dilda V, Morris TR, Naismith SL, Moore ST, Lewis SJ. Modelling freezing of gait in Parkinson’s disease with a virtual reality paradigm. Gait Posture2013;38:104–8.

Download Full-text

More Than Just Static: Dynamic Functional Connectivity Changes of the Thalamic Nuclei to Cortex in Parkinson's Disease With Freezing of Gait

Frontiers in Neurology ◽

10.3389/fneur.2021.735999 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shangpei Wang ◽

Huanhuan Cai ◽

Zong Cao ◽

Chuan Li ◽

Tong Wu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Functional Connectivity ◽

Resting State ◽

Freezing Of Gait ◽

Thalamic Nuclei ◽

Temporal Dynamic ◽

Cortical Areas ◽

Medial Geniculate ◽

The Right

Background: The thalamus is not only a key relay node of the thalamocortical circuit but also a hub in the regulation of gait. Previous studies of resting-state functional magnetic resonance imaging (fMRI) have shown static functional connectivity (FC) between the thalamus and the cortex are disrupted in Parkinson's disease (PD) patients with freezing of gait (FOG). However, temporal dynamic FC between the thalamus and the cortex has not yet been characterized in these patients.Methods: Fifty PD patients, including 25 PD patients with FOG (PD-FOG) and 25 PD patients without FOG (PD-NFOG), and 25 healthy controls (HC) underwent resting-state fMRI. Seed-voxel-wise static and dynamic FC were calculated between each thalamic nuclei and other voxels across the brain using the 14 thalamic nuclei in both hemispheres as regions of interest. Associations between altered thalamic FC based on significant inter-group differences and severity of FOG symptoms were also examined in PD-FOG.Results: Both PD-FOG and PD-NFOG showed lower static FC between the right lateral posterior thalamic nuclei and right inferior parietal lobule (IPL) compared with HC. Altered FC dynamics between the thalamic nuclei and several cortical areas were identified in PD-FOG, as shown by temporal dynamic FC analyses. Specifically, relative to PD-NFOG or HC, PD-FOG showed greater fluctuations in FC between the left intralaminar (IL) nuclei and right IPL and between the left medial geniculate and left postcentral gyrus. Furthermore, the dynamics of FC between the left pulvinar anterior nuclei and left inferior frontal gyrus were upregulated in both PD-FOG and PD-NFOG. The dynamics of FC between the right ventral lateral nuclei and left paracentral lobule were elevated in PD-NFOG but were maintained in PD-FOG and HC. The quantitative variability of FC between the left IL nuclei and right IPL was positively correlated with the clinical scales scores in PD-FOG.Conclusions: Dynamic FC between the thalamic nuclei and relevant associative cortical areas involved in sensorimotor integration or cognitive function was disrupted in PD-FOG, which was reflected by greater temporal fluctuations. Abnormal dynamic FC between the left IL nuclei of the thalamus and right IPL was related to the severity of FOG.

Download Full-text