Inferior Frontal Gyrus Alterations in Freezing of Gait in Parkinson's Disease Without Evidence for Overall Hemispheric Lateralization: A Systematic Review and Activation Likelihood Estimation Meta-Analysis

Freezing of gait (FOG) is one of the most debilitating motor symptoms of Parkinson's disease (PD). Prior studies have suggested a potential right-hemispheric preference in the pathophysiology of FOG. Yet, there is limited evidence regarding which brain regions are most consistently associated with FOG and whether these alterations indeed show right-hemispheric lateralization. We aimed to identify brain regions associated with FOG based on multimodal neuroimaging findings and to examine their hemispheric lateralization. A systematic review across multiple neuroimaging modalities was performed, followed by an activation likelihood estimation (ALE) coordinate-based meta-analysis to assess convergent brain alterations in PD patients with FOG (freezers) versus those without FOG (nonfreezers). Hemispheric lateralization was assessed using the distribution of reported stereotactic coordinates. The systematic review included 108 articles, of which 33 were included in the primary ALE meta-analysis. We identified a significant convergent cluster in the right inferior frontal gyrus (IFG) pars opercularis/dorsolateral prefrontal cortex in PD freezers compared with nonfreezers. No evidence of overall hemispheric lateralization was observed based on the distribution of reported coordinates. Our findings identify the right IFG as a consistent neural correlate of FOG, potentially reflecting heightened frontal recruitment, with no clear evidence of hemispheric lateralization. The lack of further consistency in brain regions could reflect the known heterogeneity in the pathophysiology of FOG.