Neuromodulation of Cortical Targets in Freezing of Gait

ABSTRACT Freezing of gait (FOG) is a disabling feature of Parkinson's Disease (PD) with unclear underlying pathophysiology. Evidence from multimodal neuroimaging studies suggests that complex interactions between cortical and subcortical areas may occur in FOG. While noninvasive neuromodulation techniques, such as transcranial magnetic stimulation (TMS), can effectively modulate large‐scale networks involved in FOG, the development of noninvasive neuromodulation interventions is limited by an incomplete understanding of the interactions between underlying network disruptions and FOG behavior. Recent studies have brought into question whether observed network changes in FOG are truly causal or secondary, and if secondary, are they adaptive, maladaptive, or not related? Although these questions go beyond correlative analyses, neuromodulation approaches provide an opportunity to systematically alter networks involved in FOG, providing evidence of a causal relationship. Here, we present evidence from noninvasive neuromodulation interventions of multiple cortical targets and their effects on behavior. In an attempt to leverage prior work to shed light onto the pathophysiology of FOG, we provide specific definitions of key aspects of gait behavior. We also aim to provide a framework under which adaptive and maladaptive network changes can be interpreted and targeted for the development of neuromodulation interventions. We encourage the design of future neuromodulation studies to consider including multimodal outcomes that will expand our understanding of the relationship between FOG behavior and treatment related network changes.