Project 2 – Dr. Virendra Mishra

Freezing of Gait (FOG) in Parkinson's Disease (PD)

Virendra Mishra, PhD


  • Ece Bayram, MD, PhD

  • Jason Longhurst, PT, DPT

  • Karthik Sreenivasan, MS

  • Zhengshi Yang, MS


  1. Internal Mentors:
    1. Dietmar Cordes, PhD
    2. Jeffrey Cummings, MD, DSc
  2. External Mentor:
    1. Irene Litvan, MD
Video Transcript

Study of multimodal imaging and cognition in Parkinson’s disease freezing of gait

PD is the second most common neurodegenerative disorder behind AD, and is expected to double in prevalence in the next 20 years. In 2010, the national economic burden of PD exceeded $14.4 billion (approximately $22,800 per patient (Kowal, 2013 #4259) . The direct medical costs of falls among U.S. adults 65 years and older in 2000 amounted to 19.2 billion dollars. Approximately 60% of patients with PD fall each year, resulting in significant morbidity, mortality, direct and indirect medical costs. It is therefore critical to identify modifiable factors that contribute to fall risks.

Freezing of gait (FOG) remains one of the most common causes of falls, and subsequently morbidity and mortality, in PD. FOG is a brief, episodic absence or reduction of forward progression of the feet despite the intention to walk. During these episodes, patients experience a feeling that their feet are “glued” to the floor and are unable to move. FOG typically occurs when a person is starting to walk, attempting to turn, passing through narrow passages, or nearing their intended destination. PD-FOG usually occurs in the “OFF” state (the dopaminergic medication has worn ‘off’, and is no longer effective and improving PD symptoms), but can also occur in the “ON” state (while the dopaminergic medication is effective and actively improving PD symptoms). FOG is seen in other parkinsonian syndromes, normal pressure hydrocephalus, and in patients with microvascular ischemic lesions but is most commonly associated with PD. The pathophysiology behind FOG remains unclear. and subsequently there are few effective treatment modalities.

Project 2 of the COBRE CNTN will seek to elucidate the underlying pathophysiology of freezing of gait (FOG) in PD utilizing a combination of multimodal imaging, neuropsychological testing, and clinical evaluation. This multi-faceted approach will help strengthen the relationship between abnormalities identified by neuropsychological testing and underlying brain network dysfunction specific to FOG and in general. By longitudinally following PD patients with freezing of gait (PD-FOG), we will further expand on previous studies and more concretely define which networks are involved in the pathophysiology of the disorder.

Additionally, creation of a neuropsychological profile of PD-FOG will help identify PD patients at risk of developing FOG, increasing early identification of subjects for clinical trials, and potentially allowing for intervention before PD patients develop this disabling phenomenon. Ultimately, a better understanding of PD-FOG may further development of therapeutic modalities to treat this disorder.

What are the takeaways of the video? What should viewers learn from watching it?

FOG is a common, disabling aspect of PD that leads to falls and essentially paralyzes those affected. There are few effective treatments for freezing of gait. This project will help us better understand the underlying mechanisms behind FOG, and is a step towards identifying a cure for a common cause of falls in PD.

Specific Aims:

Identify the structural and functional brain connectivity patterns in PD-FOG, PD-nFOG, and HC, and evaluate progression of FOG by:

  • Comparing the structural and functional connectivity brain patterns, both at baseline and longitudinally, between the FOG and nFOG PD subgroups;
  • Develop an unbiased estimator of tract-specific diffusion-derived measures and the fractional contribution of free-water (fiso) using a multi-shell high angular and spatial resolution diffusion MRI (dMRI), and further comparing these novel diffusion-derived voxelwise measures between the two groups to understand disease pathophysiology and progression;
  • Investigate the effect of levodopa on functional connectivity pattern in the PD subgroups; and
  • Combine the novel dMRI-derived measures with conventional structural MRI and resting state functional MRI (rs-fMRI) connectivity measures, and generate a subject-level score that is predictive of FOG progression.       

Establish a correlation between the multimodal MRI-derived measures and neuropsychological profile in each PD subgroup by:

  • Correlating the MRI-derived measures with neuropsychological assessments and clinical diagnostic tests within each PD subgroups;
  • Investigating the rs-fMRI connectivity brain patterns, and the association of these patterns with reference to changes in the neuropsychological profile with and without dopaminergic medication; and
  • Understanding the global shift in the correlation of network connectivity patterns with the neuropsychological profile within each of the PD subgroups.

Internal Mentor

Dietmar Cordes, Ph.D.
Cleveland Clinic Lou Ruvo Center for Brain Health
Director, Brain Imaging Program
(Mentor: Project 1,2)

Jeffrey L. Cummings, MD, ScD
Founding Director, Cleveland Clinic Lou Ruvo Center for Brain Health
Director, Center for Neurodegeneration and Translational Neuroscience
Cleveland Clinic Lou Ruvo Center for Brain Health
(Mentor: Project 2)