The relation of eye movements to the occurrence of freezing of gait in Parkinson's disease

Juan Fernandez-Ruiz^{1

2}, Heidi C Riek³, Donald C Brien³, Brian C Coe³, David A Grimes^{4

5

6}, Anthony E Lang^{7

8

9

10}, Connie Marras^{7

9}, Mario Masellis^{11

12

13}, Richard H Swartz^{11

12}, Brian Tan¹⁴, Malcolm A Binns^{14

15}, Stephen R Arnott¹⁶; ONDRI Investigators; Douglas P Munoz^{3

17}

Collaborators, Affiliations

Collaborators

ONDRI Investigators:
Sabrina Adamo, Rob Bartha, Courtney Berezuk, Alanna Black, Michael Borrie, Susan Bronskill, Dennis Bulman, Leanne Casaubon, Ben Cornish, Sherif Defrawy, Allison Dilliott, Roger A Dixon, Sali Farhan, Frederico Faria, Julia Fraser, Morris Freedman, Mahdi Ghani, Barry Greenberg, Hassan Haddad, Ayman Hassan, Wendy Hatch, Rob Hegele, Melissa Holmes, Chris Hudson, Mandar Jog, Peter Kleinstiver, Donna Kwan, Elena Leontieva, Brian Levine, Efrem Mandelcorn, Ed Margolin, Bill McIlroy, Manuel Montero-Odasso, David Munoz, Nuwan Nanayakkara, Miracle Ozzoude, Joel Ramirez, Natalie Rashkovan, John Robinson, Ekaterina Rogaeva, Yanina Sarquis Adamson, Christopher Scott, Michael Strong, Sujeevini Sujanthan, Sean Symons, Athena Theyers, Angela Troyer, Karen Van Ooteghem, John Woulfe, Mojdeh Zamyadi

Affiliations

¹ Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de Mexico CP 04510, México.
² Instituto de Neuroetología, Universidad Veracruzana, Xalapa, CP 91190 Veracruz, México.
³ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada, K7L 3N6.
⁴ Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada, K1Z 8L6.
⁵ Departmen of Medicine,Ottawa Hospital Research Institute, Ottawa, ON, Canada, K1H 8L6.
⁶ Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.
⁷ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, University Health Network, Toronto, ON, Canada, M5T 2S8.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada, M5S 3H2.
⁹ Krembil Brain Institute, University Health Network, Toronto, ON, Canada, M5T 1M8.
¹⁰ Rossy PSP Centre, University Health Network, Toronto, ON, Canada, M5T 2S8.
¹¹ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada, M4N 3M5.
¹² Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada, M4N 3M5.
¹³ Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, M4N 3M5.
¹⁴ Rotman Research Institute, Baycrest Academy for Research and Education, North York, ON, Canada, M6A 1W1.
¹⁵ Dalla Lana School of Public Health, University of Toronto, ON, Canada, M5T 3M7.
¹⁶ Indoc Research, Toronto, ON, Canada, M5H 3W4.
¹⁷ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada, K7L 3N6.

PMID: 41169272
PMCID: PMC12569761
DOI: 10.1093/braincomms/fcaf402

The relation of eye movements to the occurrence of freezing of gait in Parkinson's disease

Juan Fernandez-Ruiz et al. Brain Commun. 2025.

. 2025 Oct 15;7(5):fcaf402.

doi: 10.1093/braincomms/fcaf402. eCollection 2025.

Authors

Collaborators

ONDRI Investigators:
Sabrina Adamo, Rob Bartha, Courtney Berezuk, Alanna Black, Michael Borrie, Susan Bronskill, Dennis Bulman, Leanne Casaubon, Ben Cornish, Sherif Defrawy, Allison Dilliott, Roger A Dixon, Sali Farhan, Frederico Faria, Julia Fraser, Morris Freedman, Mahdi Ghani, Barry Greenberg, Hassan Haddad, Ayman Hassan, Wendy Hatch, Rob Hegele, Melissa Holmes, Chris Hudson, Mandar Jog, Peter Kleinstiver, Donna Kwan, Elena Leontieva, Brian Levine, Efrem Mandelcorn, Ed Margolin, Bill McIlroy, Manuel Montero-Odasso, David Munoz, Nuwan Nanayakkara, Miracle Ozzoude, Joel Ramirez, Natalie Rashkovan, John Robinson, Ekaterina Rogaeva, Yanina Sarquis Adamson, Christopher Scott, Michael Strong, Sujeevini Sujanthan, Sean Symons, Athena Theyers, Angela Troyer, Karen Van Ooteghem, John Woulfe, Mojdeh Zamyadi

Affiliations

¹ Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de Mexico CP 04510, México.
² Instituto de Neuroetología, Universidad Veracruzana, Xalapa, CP 91190 Veracruz, México.
³ Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada, K7L 3N6.
⁴ Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada, K1Z 8L6.
⁵ Departmen of Medicine,Ottawa Hospital Research Institute, Ottawa, ON, Canada, K1H 8L6.
⁶ Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada, K1H 8M5.
⁷ Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, University Health Network, Toronto, ON, Canada, M5T 2S8.
⁸ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada, M5S 3H2.
⁹ Krembil Brain Institute, University Health Network, Toronto, ON, Canada, M5T 1M8.
¹⁰ Rossy PSP Centre, University Health Network, Toronto, ON, Canada, M5T 2S8.
¹¹ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada, M4N 3M5.
¹² Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada, M4N 3M5.
¹³ Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, M4N 3M5.
¹⁴ Rotman Research Institute, Baycrest Academy for Research and Education, North York, ON, Canada, M6A 1W1.
¹⁵ Dalla Lana School of Public Health, University of Toronto, ON, Canada, M5T 3M7.
¹⁶ Indoc Research, Toronto, ON, Canada, M5H 3W4.
¹⁷ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada, K7L 3N6.

PMID: 41169272
PMCID: PMC12569761
DOI: 10.1093/braincomms/fcaf402

Abstract

Freezing of gait is a debilitating motor symptom in Parkinson's disease that significantly increases fall risk and impairs quality of life. The poorly understood pathophysiology of freezing of gait presents challenges for early prediction and therapeutic intervention. This prospective study investigated whether eye movement abnormalities, specifically in the anti-saccade paradigm, could predict freezing of gait onset in Parkinson's disease patients over a two-year follow-up period. We analysed longitudinal data from the Ontario Neurodegenerative Disease Research Initiative, focusing on Parkinson's disease patients without freezing of gait at baseline who underwent comprehensive clinical evaluations and eye movement recordings. Anti-saccade reaction time and error ratio, combined with clinical measures including right upper extremity rigidity, demonstrated significant predictive value for freezing of gait development within two years. These findings suggest that eye movement deficits and upper limb rigidity emerge years before freezing of gait onset, indicating a prodromal phase in freezing of gait pathogenesis. The predictive relationship between these measures supports the hypothesis of shared neural substrates, potentially involving the mesencephalic locomotor region, in the development of both oculomotor dysfunction and gait freezing episodes.

Keywords: Parkinson's disease; anti-saccade; eye movement biomarkers; freezing of gait; predictive markers.

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Conflict of interest statement

M.M. holds grants unrelated to this work from the Canadian Institutes of Health Research (CIHR), Washington University, the Women’s Brain Health Initiative, and Brain Canada as part of the EU Joint Program for Neurodegenerative Disease Research. M.M. also has clinical trial contracts with Roche and Alector; has received consulting fees from Eisai Canada, Eli Lilly Canada, and Novo Nordisk Canada; received royalties from the Henry Stewart Talks; has received payments from MINT Memory Clinics and the ECHO Dementia Series; and holds unpaid Scientific Advisory Board roles with the Alzheimer’s Society Canada and Parkinson Canada. R.S. is supported by the Bastable-Potts Chair in Stroke Research, holds stock ownership in FollowMD Inc., and has served on an advisory board for Roche within the last two years. D.A.G. has received honoraria for speaking engagements with Ipsen and consulting for AbbVie, Biogen Canada, and Knight Therapeutics. D.A.G. has also participated in clinical trials funded by CIHR, Cerevel Therapeutics, Hoffmann-La Roche, UCB Biopharma, and Bial R&D Investments. All other authors report no competing interests.

Figures

**Figure 1**
**Normalized metrics that differed between groups at the first visit.** Group effects (n-FOG (n = 10) and y-FOG (n = 11)) are from the primary models (MANCOVA with variable-level follow-up tests, adjusted for covariates as specified in Methods). Panels display individual data points where each dot represents one participant; central horizontal lines indicate medians. A-E, Eye-movement variables: (A) PS amplitude (P = 0.02, η² = 0.12); (B) AS reaction time (P = 0.03, η² = 0.2); (C) AS amplitude (P = 0.02, η² = 0.24); (D) AS express error (P = 0.02, η² = 0.23); (E) AS error (P = 0.02, η² = 0.23). F-J, Motor variables: (F) tremor (P = 0.01, η² = 0.29); (G) left hand postural tremor (P = 0.01, η² = 0.25); (H) left hand tremor amplitude (P = 0.01, η² = 0.35); (I) right arm rigidity (P = 0.02, η² = 0.23); (J) right finger tapping (P = 0.03, η² = 0.21). PS: pro-saccade; AS: antisaccade.

**Figure 2**
**Receiver operating characteristic (ROC) curves for the only variables predicting freezing of gate (FOG).** The dots on each curve mark the optimal cut-off points as determined by Youden's Index. (A) Eye-movement variables. (B) Clinical variables. AUC: area under the curve. Left panel lines are shown jittered for clarity purposes.

See this image and copyright information in PMC

References

1. Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primer. 2017;3(1):1–21. - PubMed
1. Nutt JG, Bloem BR, Giladi N, Hallett M, Horak FB, Nieuwboer A. Freezing of gait: Moving forward on a mysterious clinical phenomenon. Lancet Neurol. 2011;10(8):734–744. - PMC - PubMed
1. Chan F, Armstrong IT, Pari G, Riopelle RJ, Munoz DP. Deficits in saccadic eye-movement control in Parkinson’s disease. Neuropsychologia. 2005;43(5):784–796. - PubMed
1. Crawford TJ, Henderson L, Kennard C. Abnormalities of nonvisually-guided eye movements in Parkinson’s disease. Brain. 1989;112(6):1573–1586. - PubMed
1. Lee MS, Rinne JO, Marsden CD. The pedunculopontine nucleus: Its role in the genesis of movement disorders. Yonsei Med J. 2000;41(2):167–184. - PubMed

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The relation of eye movements to the occurrence of freezing of gait in Parkinson's disease

Collaborators

Affiliations

The relation of eye movements to the occurrence of freezing of gait in Parkinson's disease

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources