Freezing of Gait in Parkinson's Disease: Invasive and Noninvasive Neuromodulation

Abstract

Introduction: Freezing of gait (FoG) is one of the most disabling yet poorly understood symptoms of Parkinson's disease (PD). FoG is an episodic gait pattern characterized by the inability to step that occurs on initiation or turning while walking, particularly with perception of tight surroundings. This phenomenon impairs balance, increases falls, and reduces the quality of life.

Materials and methods: Clinical-anatomical correlations, electrophysiology, and functional imaging have generated several mechanistic hypotheses, ranging from the most distal (abnormal central pattern generators of the spinal cord) to the most proximal (frontal executive dysfunction). Here, we review the neuroanatomy and pathophysiology of gait initiation in the context of FoG, and we discuss targets of central nervous system neuromodulation and their outcomes so far. The PubMed database was searched using these key words: neuromodulation, freezing of gait, Parkinson's disease, and gait disorders.

Conclusion: Despite these investigations, the pathogenesis of this process remains poorly understood. The evidence presented in this review suggests FoG to be a heterogenous phenomenon without a single unifying pathologic target. Future studies rigorously assessing targets as well as multimodal approaches will be essential to define the next generation of therapeutic treatments.

Keywords: Deep Brain Stimulation; Parkinsons disease; freezing; gait.

Figure 1.

Supraspinal locomotion centers and areas implicated in freezing of gait. Schematic drawing of the supraspinal motor network of locomotor control. Cortical signals convey motor commands (via the direct/indirect and hyperdirect pathways) to the basal ganglia which then conveys information to the mesencephalic locomotor region (MLR). The MLR represents a crossroad of information coming from the basal ganglia and the cerebellum, which receives sensory feedback from ascending spinal pathways (blue arrows). Several of these regions are implicated in Parkinson’s disease (PD) postural instability and gait disorders including freezing of gait. Feedforward motor commands are displayed in green (activating) and red (inhibiting). CLR, cerebellar locomotion region; CPGs, central pattern generators; GPi, globus pallidus internus; M1, primary motor cortex; MLR/PPN, mesencephalic locomotor region/pedunculopontine nucleus; PMRF, pontomedullary reticular formation; SLR/STN, subthalamic locomotor region/subthalamic nucleus; SMA/PM, supplementary motor area/premotor cortex.

Figure 2.

Invasive and non-invasive therapies for freezing of gait. a. Noninvasive interventions include TMS, tDCS, and nVNS. Invasive interventions include DBS and SCS. b–d. Three-dimensional views of FoG DBS targets. Reconstructions were created in Lead-DBS using available MNI-space subcortical atlases (–100). b. Frontal top view, (c) sagittal view, and (d) posterior oblique view of DBS electrodes targeting the GPi, STN, and the MLR (CnF in cyan and PPN in fuchsia). CnF, cuneiform nucleus; PPN, pedunculopontine nucleus; SN, substantia nigra; STN, subthalamic nucleus.