Freezing of gait: understanding the complexity of an enigmatic phenomenon

Abstract

Diverse but complementary methodologies are required to uncover the complex determinants and pathophysiology of freezing of gait. To develop future therapeutic avenues, we need a deeper understanding of the disseminated functional-anatomic network and its temporally associated dynamic processes. In this targeted review, we will summarize the latest advances across multiple methodological domains including clinical phenomenology, neurogenetics, multimodal neuroimaging, neurophysiology, and neuromodulation. We found that (i) locomotor network vulnerability is established by structural damage, e.g. from neurodegeneration possibly as result from genetic variability, or to variable degree from brain lesions. This leads to an enhanced network susceptibility, where (ii) modulators can both increase or decrease the threshold to express freezing of gait. Consequent to a threshold decrease, (iii) neuronal integration failure of a multilevel brain network will occur and affect one or numerous nodes and projections of the multilevel network. Finally, (iv) an ultimate pathway might encounter failure of effective motor output and give rise to freezing of gait as clinical endpoint. In conclusion, we derive key questions from this review that challenge this pathophysiological view. We suggest that future research on these questions should lead to improved pathophysiological insight and enhanced therapeutic strategies.

Cueing Paradigms to Improve Gait and Posture in Parkinson’s Disease: A Narrative Review

“…A common consequence of striatal dopamine loss is attenuation of the transfer of critical information to the basal ganglia which leads to a decrease in the ability to detect relevant internal sensory and or movement cues [1,21,22]. Such a disruption of information flow to the basal ganglia may worsen impaired movement selection and sequencing in striatum with dopamine loss thereby resulting in gait impairments [23]. The pattern of deficits in people with PD is consistent with a disruption of this integration mechanism.…”

“…Sci. 2020, 10, x FOR PEER REVIEW 3 of 18 the basal ganglia may worsen impaired movement selection and sequencing in striatum with dopamine loss thereby resulting in gait impairments [23]. The pattern of deficits in people with PD is consistent with a disruption of this integration mechanism.…”

Anti-Gravity Treadmill Training for Freezing of Gait in Parkinson’s Disease

“…The pathophysiology of FoG is complex and not fully understood where a network of cortical and subcortical structures seems to dysfunction leading to a multilevel neuronal integration failure [ 14 ]. We hypothesize that attenuation of ground reaction forces provided by the machine may lead to better integration of neuronal motor circuits with the patient regaining certain motor abilities.…”

“…We hypothesize that attenuation of ground reaction forces provided by the machine may lead to better integration of neuronal motor circuits with the patient regaining certain motor abilities. It is also possible that patients may enhance neuronal compensatory mechanisms with improvement in gait [ 14 ]. The antigravity treadmill training has shown several benefits in children with cerebral palsy, including: improved muscle stiffness, decreased reflex hyperexcitability and enhanced corticostriatal tract function [ 15 ].…”

Die Geschichte des ‚Freezing-of-gait‘ beim Parkinson-Syndrom – vom Phänomen zum Symptom

“…Daneben scheint auch die Niederfrequenzstimulation (60 Hz) der klassischen Hochfrequenztimulation mit 130 Hz in der Behandlung des FOG überlegen zu sein, was anhand verschiedener, teils randomisierter doppelblinder Studien gezeigt wurde [58,59]. Darüber hinaus zeigte eine kombinierte STN-und SNr-Stimulation (SNr = Substantia nigra pars reticulata) positive Effekte auf FOG und war dabei der konventionellen STN-Stimulation bezüglich Freezing überlegen [60]. Dieses Ergebnis der ersten randomisierten und kontrollierten Studie wird gerade in einer multizentrischen Studie im Parallel-Gruppen-Design validiert.…”