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Background: Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD). Objective: The aim was to reveal the mechanisms of "OFF‐period" FOG (OFF‐FOG) and "levodopa‐unresponsive" FOG (ONOFF‐FOG) in PD. Methods: We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF‐FOG, 15 PD patients with OFF‐FOG, and 15 PD patients without FOG (Non‐FOG) in "ON" and "OFF" medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF‐FOG patients. Results: In "OFF" condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF‐FOG and OFF‐FOG) compared to Non‐FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in "ON" condition, SICI in ONOFF‐FOG patients reduced compared to OFF‐FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF‐FOG patients, and high‐frequency repetitive TMS distinctly improved gait in ONOFF‐FOG patients, accompanied by enhanced SICI. Conclusions: Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF‐FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Freezing of gait (FOG) in Parkinson's disease (PD), especially the "L-dopa-unresponsive" subtype, is associated with the dysfunction of non-dopaminergic circuits. Objective: We sought to determine whether cortical sensorimotor inhibition evaluated by short-latency afferent inhibition (SAI) related to cholinergic and gamma-aminobutyric acid (GABA)-ergic activities is impaired in PD patients with L-dopa-unresponsive FOG (ONOFF-FOG). Methods: SAI protocol was performed in 28 PD patients with ONOFF-FOG, 15 PD patients with "off" FOG (OFF-FOG), and 25 PD patients without FOG during medication "on" state. Additionally, 10 ONOFF-FOG patients underwent SAI testing during both "off" and "on" states. Twenty healthy controls participated in this study. Gait was measured objectively using a portable Inertial Measurement Unit system, and participants performed 5-meter Timed Up and Go single- and dual-task conditions. Spatiotemporal gait characteristics and their variability were determined. FOG manifestations and cognition were assessed with clinical scales. Results: Compared to controls, PD patients without FOG and with OFF-FOG, ONOFF-FOG PD patients showed significantly reduced SAI. Further, dopaminergic therapy had no remarkable effect on this SAI alterations in ONOFF-FOG. Meanwhile, OFF-FOG patients presented decreased SAI only relative to controls. PD patients with ONOFF-FOG exhibited decreased gait speed, stride length, and increased gait variability relative to PD patients without FOG and controls under both walking conditions. For ONOFF-FOG patients, significant associations were found between SAI and FOG severity, gait characteristics and variability. Conclusion: Reduced SAI was associated with severe FOG manifestations, impaired gait characteristics and variability in PD patients with ONOFF-FOG, suggesting the impaired thalamocortical cholinergic-GABAergic SAI pathways underlying ONOFF-FOG. [ABSTRACT FROM AUTHOR]

Introduction: Freezing of gait is a common complaint in patients with Parkinson's disease (PD). However, the neural bases of freezing of gait in PD remain uncertain. Existing studies on PD patients with freezing of gait (PD-FOG+) have reported damage of the corpus callosum, the largest commissural bundle of the brain. Thus, in this study we explored homotopic connectivity to investigate FOG-related interehemispheric alterations METHODS: A total of 21 PD-FOG + patients, 33 PD patients without freezing of gait (PD-FOG-), and 24 matched healthy controls were recruited. All PD patients were evaluated via the FOG questionnaire (FOGQ) and all subjects had a resting state functional magnetic resonance imaging (rs-fMRI) scan. The pattern of the homotopic connectivity was measured with the voxel-mirrored homotopic connectivity (VMHC) approach.Result: The PD-FOG + patients showed decreased VMHC values in the inferior parietal lobe (IPL) compared to both PD-FOG-patients and healthy controls. In PD-FOG + patients, the mean VMHC values in the IPL were negatively correlated with the FOGQ scores. Receiver operating characteristic curves analyses revealed that the VMHC in the IPL had discriminatory function distinguishing PD-FOG + patients from PD-FOG-patients or healthy controls.Conclusion: Decreased VMHC values of PD-FOG + patients relative to PD-FOG- and healthy controls in IPL maybe a unique feature for PD-FOG+ and it may have the ability to separate PD-FOG + patients from PD-FOG- and healthy controls. [ABSTRACT FROM AUTHOR]

Freezing of gait (FOG) is an intractable and paroxysmal gait disorder that seriously affects the quality of life of Parkinson's disease (PD) patients. Emerging studies have reported abnormal brain activity of distributed networks in FOG patients, whereas ignoring the intrinsic dynamic fluctuations of functional connectivity. The purpose of this study was to examine the dynamic functional network connectivity (dFNC) of PD-FOG. In total, 52 PD patients with FOG (PD-FOG), 73 without FOG (PD-NFOG) and 38 healthy controls (HCs) received resting state functional magnetic resonance imaging (rs-fMRI). Sliding window method, k-means clustering and graph theory analysis were employed to retrieve dynamic characteristics of PD-FOG. Partial correlation analysis was conducted to verify whether the dFNC was related to freezing gait severity. Seven brain networks were identified and configured into seven states. Compared to PD-NFOG, significant spatial pattern was identified for state 2 in freezers, showing increased functional coupling between default mode network (DMN) and basal ganglia network (BG), as a concrete manifestation of increased precuneus-caudate coupling. The mean dwell time and fractional window of state 2 had a positive correlation with FOG severity. Furthermore, PD-FOG group exhibited lower variance in nodal efficiency of independent components (IC) 7 (left precuneus). Our study suggested that aberrant coupling of precuneus-caudate and disrupted variability of precuneus efficiency might be associated to the neural mechanisms of FOG. • altered coupling of DMN-BG. • decreased variance in Ne of precuneus. • visuospatial overload. [ABSTRACT FROM AUTHOR]