Imaging the neural underpinnings of freezing of gait in Parkinson's disease

Abstract

Freezing of gait (FoG) is a paroxysmal and sporadic gait impairment that severely affects PD patients' quality of life. This review summarizes current neuroimaging investigations that characterize the neural underpinnings of FoG in PD. The review presents and discusses the latest advances across multiple methodological domains that shed light on structural correlates, connectivity changes, and activation patterns associated with the different pathophysiological models of FoG in PD. Resting-state fMRI studies mainly report cortico-striatal decoupling and disruptions in connectivity along the dorsal stream of visuomotor processing, thus supporting the 'interference' and the 'perceptual dysfunction' models of FoG. Task-based MRI studies employing virtual reality and motor imagery paradigms reveal a disruption in functional connectivity between cortical and subcortical regions and an increased recruitment of parieto-occipital regions, thus corroborating the 'interference' and 'perceptual dysfunction' models of FoG. The main findings of fNIRS studies of actual gait primarily reveal increased recruitment of frontal areas during gait, supporting the 'executive dysfunction' model of FoG. Finally, we discuss how identifying the neural substrates of FoG may open new avenues to develop efficient treatment strategies.

Keywords: Gait impairment; Locomotor regions; Motor imagery; Neuroimaging; Virtual reality.

Fig. 1

A physiological model of gait and pathophysiological model of freezing of gait (FoG). The normal control of gait requires coordinated activity between the cortex, the basal ganglia (BG), and the cerebellum to modulate the brainstem locomotor regions’ output. In a healthy system (a), an efficient initiation, execution, and termination of the desired movement are achieved via the excitation of the target motor plan (direct pathway) and the inhibition of competing motor plans (hyper-direct and indirect pathways). Before activating a target motor system, the baseline inhibition is increased in this system via the hyper-direct pathway that projects directly from the SMA to the STN. The target system is later released from this inhibition through its excitation via the striatum’s direct pathway to the GPi, resulting in the initiation and execution of the planned movement. The cessation of the movement is mediated by the target motor system’s re-inhibition via the indirect pathway from the striatum to the GPe and STN. This coordinated excitation and inhibition allow the BG to modulate the motor output of the locomotor regions in the brainstem and cerebellum to produce the desired movement. However, in Parkinson’s disease (b) this coordination is compromised, leading to a sustained over-inhibition (increased inhibition via the hyper-direct and indirect pathways, and decreased disinhibition via the direct pathway) of the brainstem structures via the GPi/SNr that hinders the initiation and execution of movement resulting in FoG. FoG can occur at the initiation stage (possibly due to sustained baseline inhibition via the hyper-direct pathway and decreased direct pathway disinhibition) or during an ongoing movement (possibly due to temporally abrupt re-inhibition via the indirect pathway and decreased disinhibition of direct pathway). CLR: cerebellar locomotor region, CMA: cingulate motor area, CPG: central pattern generators, D1: excitatory dopamine receptor, D2: inhibitory dopamine receptor, GPe: globus pallidus externus, GPi: globus pallidus internus, M1: primary motor cortex, MLR: mesencephalic locomotor region, PM: premotor cortex, PPN: pedunculopontine nucleus, PRF: pontine reticular formation, SMA: supplementary motor area, SNr: substantia nigra pars reticulata, STN: subthalamic nucleus, Thal: thalamus, vMRF: ventromedial reticular formation.

Fig. 2

Schematic depiction of the main pathophysiological models of freezing of gait (FoG) in Parkinson’s disease. The interference model (presented by blue arrows) posits that FoG is due to a failure in crosstalk between several cortical areas (cognitive, motor, and limbic) and the basal ganglia (BG). This dysfunction in crosstalk exerts a higher load on the BG-SMA loop for internally-generated movements, which eventually leads to the disruption of the BG-SMA loop and the ensuing lack of gait automaticity. This model accounts for episodes of FoG that occur during multitasking while walking. The perceptual dysfunction model (presented by the green arrow) proposes that FoG results from a malfunction along the dorsal stream of visuomotor processing. Thus, visual input is not adequately transferred from occipital areas to somatosensory areas and later to frontal areas responsible for generating an appropriate motor plan. This model accounts for the failure in adapting the ongoing locomotion in response to changes in the environment (e.g., crossing doorways), which can manifest in an episode of FoG. The executive dysfunction model (presented by the orange arrow) considers FoG to result from a specific decoupling between cognitive areas in the frontal lobe and the BG. According to this model, executive control areas are heavily recruited to compensate for the lack of gait automaticity, which can account for FoG during cognitively demanding dual tasks, such as obstacle avoidance while walking. All these different mechanisms proposed by the models of FoG eventually overwhelm the limited processing capacity of the striatum in PD and consequently lead to a hyperactive GPi that overly inhibits brainstem (MLR/PPN) and cerebellar (CLR) structures, eventually producing episodes of FoG. Note that this schematic illustration does not cover the ‘decoupling’ and ‘abnormal gait pattern generation’ models of FoG, given that none of the discussed imaging studies provide corroborating results to support these models. (Figure created with BioRender.com) BG: basal ganglia, CLR: cerebellar locomotor region, D1/2: dopamine receptors, FoG: freezing of gait, GPi/e: globus pallidus internus/externus, MLR: mesencephalic locomotor region, PPN: pedunculopontine nucleus, SMA: supplementary motor area, STN: subthalamic nucleus.