A systematic review on exercise and training-based interventions for freezing of gait in Parkinson's disease

Abstract

Freezing of gait (FOG) in Parkinson's disease (PD) causes severe patient burden despite pharmacological management. Exercise and training are therefore advocated as important adjunct therapies. In this meta-analysis, we assess the existing evidence for such interventions to reduce FOG, and further examine which type of training helps the restoration of gait function in particular. The primary meta-analysis across 41 studies and 1838 patients revealed a favorable moderate effect size (ES = -0.37) of various training modalities for reducing subjective FOG-severity (p < 0.00001), though several interventions were not directly aimed at FOG and some included non-freezers. However, exercise and training also proved beneficial in a secondary analysis on freezers only (ES = -0.32, p = 0.007). We further revealed that dedicated training aimed at reducing FOG episodes (ES = -0.24) or ameliorating the underlying correlates of FOG (ES = -0.40) was moderately effective (p < 0.01), while generic exercises were not (ES = -0.14, p = 0.12). Relevantly, no retention effects were seen after cessation of training (ES = -0.08, p = 0.36). This review thereby supports the implementation of targeted training as a treatment for FOG with the need for long-term engagement.

Fig. 1. Theoretical model of gait control in healthy persons and PD patients with FOG.

a In healthy individuals, gait automaticity is achieved via processing across dorsal cortico-striatal-thalamo-cerebellar-brainstem neural circuits. Segregation of the motor circuit from other, i.e., sensory, limbic, and cognitive circuits, allows consecutive processing of multiple inputs without interference, ensuring normal gait automaticity. Note, however, that gait is not always automatically controlled. Attentional control will be called upon in gait during complex circumstances. The need for attentional gait control increases with older age and more so in pwPD. b Following substantial degeneration of nigral-striatal dopaminergic neurons (indicated by gray coloring in the dorsal striatum) already prominent in early PD, gait automaticity becomes impaired. External sensory input and cognitive control come on to maintain gait control (as indicated by the increase in black arrows, modeling greater inter-circuit connectivity). Occasional FOG occurs when processing demands exceed the combined capacity of motor and compensatory circuits. Limbic input to the striatum (indicated by red arrow) may increase interference and exacerbate FOG. c The progression of nigral-striatal neurodegeneration inherent to moderate PD heavily affects processing across the motor circuit (indicated by dotted arrows), increasing the dependency on compensatory circuits. The risk for interference during gait becomes higher, resulting in regular episodes of FOG. d In the advanced stages, extra-nigral neuropathology starts to affect processing across the compensatory circuits (indicated by the gray dotted arrows), resulting in severe gait disability and frequent FOG.

Fig. 2. Flowchart of the systematic article selection strategy.

From 3694 articles identified from the search strategy, a total of 50 articles were included for review. Red boxes indicate exclusions of articles during each of the following screening stages: duplicate removal, title, abstract, full-text. Reasons for exclusion are shown inside the red boxes. Green box indicates inclusion.

Fig. 3. Primary analysis comparing all types of training/exercise interventions against any type of control group.

The studies are arranged per weight of the study determined by sample size; *significant outliers removed in the sensitivity analysis.

Fig. 4. Secondary analysis comparing the effect of all types of training/exercise interventions against passive control groups.

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 5. Secondary analysis comparing the effect of all types of training/exercise against active control groups.

The studies are arranged per weight of the study as based on sample size.

Fig. 6. Secondary analysis comparing all types of training/exercise interventions against any type of control group in studies enrolling the only PD with FOG (i.e., freezers).

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 7. Secondary analysis comparing effects of category A interventions aimed directly at the alleviation of FOG episodes or FOG-provoking triggers against any type of control group.

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 8. Secondary analysis comparing effects of category B interventions aimed at the underlying correlates of FOG against any type of control group.

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 9. Secondary analysis comparing category C “generic exercise” interventions against any type of control group.

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 10. Secondary analysis comparing retention effects of all types of training/exercise interventions against any type of control group.

The studies are arranged per weight of the study as based on sample size; *significant outliers removed in the sensitivity analysis.

Fig. 11. Theoretical framework for selecting the type of exercise/training in PD using a simple selection criteria, namely the self-reported frequency of FOG.

Blue shaded areas indicate when this category of intervention is recommended. The red arrow represents the current progression of worsening FOG severity. The green dotted arrow represents the hypothesized attenuated progression of FOG severity that may be achieved by following this framework. Note that the intensity of generic exercise will likely need to be reduced when FOG-related interventions are offered due to time, energy, and resource constraints. There will also be an increasing need for supervised training by a therapist as the disease progresses and FOG becomes more regular.