Mari Reis.mp4 ##TOP##

In the mechanism section, we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG. In the risk factor section, gait disorders, PIGD phenotype, lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence. In the treatment section, we summarized the clinical trials of pharmacological and non-pharmacological treatments. Despite the limited effectiveness of current medications for FOG, especially levodopa resistant FOG, there were some drugs that showed promise such as istradefylline and rasagiline. Non-pharmacological treatments encompass invasive brain and spinal cord stimulation, noninvasive repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS), and physiotherapeutic approaches including cues and other training strategies. Several novel therapeutic strategies seem to be effective, such as rTMS over supplementary motor area (SMA), dual-site DBS, spinal cord stimulation (SCS) and VNS. Of physiotherapy, wearable cueing devices seem to be generally effective and promising.

Mari Reis.mp4

Our understanding towards mechanism in FOG remains incomplete, and treatment of FOG is perceived by clinicians as a very challenging task. Several hypotheses have been proposed to explain the freezing phenomenon and many approaches have been applied to treat FOG. In this review, firstly, we summarized the physiology of gait control, and briefly introduced the mechanism hypotheses of FOG. Secondly, we summarized the risk factors of FOG to facilitate FOG screening in consideration of early therapeutic interventions to delay or even prevent the onset of FOG. Thirdly, various treatment approaches exist, including pharmacological and non-pharmacological treatments. Non-pharmacological treatments including invasive brain and spinal cord stimulation, noninvasive brain and vagus nerve stimulation, and physiotherapeutic approaches. Clinical trials involving various therapeutic strategies were summarized in this review. In addition, the limitations and recommendations for future research design were also discussed.

Several hypotheses have been proposed based on the FOG phenotype and mechanistic studies. Nieuwboer et al. [11] summarized the pathological mechanisms in the following four models: a) The threshold model [12]: Compared with non-freezers, patients with FOG present significant gait disorders such as reduced stride amplitude, impaired gait coordination and increased variability of step timing. This model assumes that when these motor deficits accumulate to a point of motor breakdown, then FOG occurs. b) The interference model [13]: The relationship of motor, cognitive and limbic circuits is proposed as both competing and complimentary. As dopamine neurons are mostly depleted in PD patients, concurrent processing of cognitive and/or limbic information during motor task will overload the information processing capacity within basal ganglia, thus leading to disordered neuronal crosstalk between these circuits. The interference between neural circuits would explain the phenomena that increasing cognitive load while performing a dual task will break down the locomotion. c) The cognitive model [14]: This modal emphasized the conflict-resolution deficit, which is one aspect of executive dysfunction. Under normal condition, people will prevent premature action and delay the response selection until resolving the conflict. In contrast, patients with FOG fail to process response conflict, impose faster response decision but with greater incongruence, thus FOG is triggered. d) The decoupling model [15]: This model regarded FOG as a disconnection between pre-planned motor program and motor response. These models and hypotheses explained FOG from various perspectives. Albeit incomplete and can only partially interpret the pathophysiology and clinical phenotype of FOG, it is worth noting that these models are helpful for better understanding and characterizing FOG, and provide clues for further research exploration. More importantly, based on these models, behavior strategies can be invented and implemented for FOG treatment.

This review included the prospective studies that followed early-stage PD patients over time and the retrospective studies that clearly recorded the clinical manifestation prior to FOG onset. Many studies identified FOG related motor and non-motor symptoms by utilizing cross-section data to compare the clinical symptoms between freezers and non-freezers. Those studies were excluded as they cannot differentiate the symptoms prior to FOG from the accompanying symptoms of FOG. A total of 11 longitudinal follow-up studies were reviewed and summarized (Table 1). For these studies, cox proportional-hazards regression analyses [16, 17, 20, 26] or logistic regression analysis [18, 19, 22,23,24,25] were performed to identify the factors predictive of FOG except one study that used generalized estimating equations [21]. Here, we elaborated the risk factors including demographic information, motor symptoms, non-motor symptoms, neuroimaging, fluid parameters, and medication use. Current limitations and recommendations for future researches will also be discussed. A list of the evidence supporting and refuting the following variables as risk factors of FOG was provided in Table 2. 041b061a72