Journal
BRAIN
Volume 143, Issue -, Pages 14-30Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz314
Keywords
freezing of gait (FoG); Parkinson's disease; stimulation; neurophysiology; genetics
Categories
Funding
- International Parkinson and Movement Disorder Society
- Research Foundation Flanders
- Michael J Fox Foundation
- German Research Council (DFG) [WE5375/1-1, WE5375/1-3]
- NIH [R01MH113929, P01 NS015655, RO1 NS070856, P50 NS091856]
- Nancy Lurie Marks Foundation
- Dystonia Medical Research Foundation
- Department of Veterans Affairs [I01 RX001631]
- Michael J. Fox Foundation
- Curtis Family Foundation
- Sartain Lanier Family Foundation
- European Commission
- King Baudouin Funds
- KU Leuven Internal Funds
- Jacques and Gloria Gossweiler Foundation
- NINDS
- Australian NHMRC-ARC Dementia Fellowship [1110414]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [ZIANS003031] Funding Source: NIH RePORTER
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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 its temporally associated dynamic processes. In this targeted review, we wilt 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 pachophysiological insight and enhanced therapeutic strategies.
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