Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study

Abstract

BackgroundDysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD).ObjectiveThe aim was to reveal the mechanisms of “OFF‐period” FOG (OFF‐FOG) and “levodopa‐unresponsive” FOG (ONOFF‐FOG) in PD.MethodsWe 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.ResultsIn “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.ConclusionsMotor 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.

Motor Cortex Disinhibition Is Not Associated with Freezing of Gait in Parkinson's Disease

“…1 Still, motor cortex disinhibition is highly variable across patients, and the origin and significance of this variability remain unclear. As a possible solution for the variability puzzle, a recent study suggested that motor cortex disinhibition of the hand area in PD may be specifically associated with freezing of gait (FOG), 6 which becomes particularly prevalent in advanced stages of PD. But the association is at odds with the fact that motor cortex disinhibition does not seem to progress in advanced compared to early stages of PD.…”

Disinhibition Is an Essential Network Motif Coordinated by GABA Levels and GABA B Receptors

“…In addition to various physiological processes, disinhibition has been proposed as a pathophysiological substrate of various diseases. In Parkinson's disease, disinhibition in the primary motor cortex has been suggested as one of the first manifestations [70] and is correlated with freezing and gait impairment [71]. Obesity is associated with disinhibition of the orbitofrontal cortex.…”