# Neuromodulation of Cortical Targets in Freezing of Gait

## TL;DR

This paper explores how noninvasive brain stimulation can help understand and treat freezing of gait in Parkinson's Disease by targeting specific brain regions.

## Contribution

The paper introduces a systematic framework for interpreting network changes in freezing of gait using neuromodulation.

## Key findings

- Noninvasive neuromodulation can alter cortical networks involved in freezing of gait behavior.
- Different stimulation parameters can reveal adaptive or maladaptive contributions of cortical targets.
- Multimodal outcomes are needed to better understand the relationship between network changes and gait behavior.

## 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.

Above is a graphical representation of a systematic approach to evaluate the role of cortical regions in the development of FOG using neuromodulation. Systematic neuromodulation of cortical targets can inform whether these network changes are primary (causal) or secondary. (A) In this example rTMS is focused on the engagement of cortical brain regions (red) responsible for volitional control of gait (SMA; Supplemental Motor Area, CMA; Cingulate Motor Area, M1; Primary Motor Cortex). These regions have connectivity with locomotor centers important for gait automaticity (SLR; Subthalamic Locomotor Region, CLR; Cerebellar Locomotor Region, and PPN: Pedunculopontine Nucleus). This ultimately impacts downstream central pattern generators (CPGs) in the spinal cord which regulate gait cycles. (B) In this example, specific rTMS parameters (1 Hz, 10 Hz, cTBS, and iTBS) can be manipulated to have distinct effects on cortical circuits allowing us to infer the adaptive or maladaptive contributions of these targets. (C) In cases where there is no clear impact of neuromodulation of FOG behavior, other targets can be evaluated and alternative models of how cortex contributes to FOG can be considered. For example the crosstalk model proposes disrupted neural signals from limbic and cognitive regions in addition to motor circuits.