More than half of patients with Parkinson’s disease suffer from Freezing of gait. The symptoms of Freezing vary; some experience alternating leg tremors or a reduction in stride length to the point of shuffling, while others describe a sensation of motor blockage, as if their feet are “stuck to the floor” while the upper body continues to move.
Freezing can be triggered by various factors, situations (e.g., cognitive, emotional), and environments, such as dual-tasking (performing two actions simultaneously, like talking and walking), approaching or passing through a narrow passage or doorway, turning around, being in a crowded space, experiencing many distractions, nearing the destination point (like a sofa), or simply being in a hurry. Ultimately, Freezing increases the risk of falling.
The pathophysiology of Freezing is not well understood. What is known is that comorbidities of the disease, such as anxiety and cognitive decline, exacerbate it.
According to the authors of a review published in Parkinsonism and Related Disorders, current pharmacological and surgical treatments for Freezing of gait, such as traditional oral dopaminergic medications and deep brain stimulation (DBS), are at best only partially effective in many patients.
Here’s an interview with two of the authors of the review, Moran Gilat, PhD, postdoctoral researcher at the Department of Rehabilitation, University of Leuven in Flanders, Belgium, and Simon JG Lewis, MBBCh, BSc, FRCP, FRACP, MD, professor at the Parkinson’s Disease Research Clinic, Brain and Mind Center, University of Sydney in Australia, regarding current therapeutic challenges and potential new treatments for Freezing.
Neurological Consultant: Why do current treatments fail to adequately control Freezing?
Dr. Gilat: Freezing has only recently emerged as one of the most debilitating features of Parkinson’s.
Thus, only in the last decade has there been an increase in research studies regarding its neural bases and the limited efficacy of existing treatments (such as dopamine replacement therapies).
Furthermore, Freezing is more common in the advanced stages of Parkinson’s disease, when both nigral and extranigral pathologies spread and affect numerous neuronal circuits involved in Freezing.
However, the spread of pathology and subsequent degeneration varies among patients and is challenging to delineate, making it difficult to tailor pharmacological interventions to the neural needs of each patient.
At this advanced stage, a multidisciplinary approach between pharmacological and behavioral treatments is therefore currently the best option, although future studies should aim to find better methods to also tailor non-pharmacological interventions to each patient’s characteristics that affect the severity of Freezing of gait.
Is Freezing more difficult to treat in some patients than others?
Professor Lewis: Freezing becomes increasingly difficult to treat, especially when it becomes dopamine-resistant in the advanced stages of the disease. As Parkinson’s pathology spreads over time, more and more brain areas, which have been shown to play a role in the onset of Freezing, are affected.
For example, with disease progression, patients particularly develop cognitive deficits, especially in their executive functioning, implying frontal cortical dysfunction.
These cognitive deficits likely stem from extranigral degeneration of cholinergic and noradrenergic neurons that play a significant role in these frontal brain areas. Since executive dysfunctions are involved in the etiology of Freezing, managing these deficits becomes important to counteract cognitive decline and also prevent motor blocks.
However, as mentioned earlier, the spread of pathology and subsequent degeneration varies among patients, making it difficult to tailor pharmacological treatments and test the effects of new drugs in future clinical trials, as these require large patient groups to achieve good statistical outcomes.
However, given that Freezing in patients is triggered by different neuronal deficits, it is highly unlikely that one therapy will have a positive effect on all, as not all patients will be responsive to the therapy, depending on their neuronal deficits.
What makes treating Freezing of gait so difficult? How does disease heterogeneity/interindividual variability come into play?
Dr. Gilat: Freezing of gait in Parkinson’s is a highly heterogeneous symptom, as illustrated by the variety of situations that trigger motor blocks to different extents for each patient.
That is, some patients often get stuck when walking through doorways or when trying to turn around, while others might get stuck more commonly when performing a cognitive task, like talking while walking or when feeling anxious.
This suggests that each patient likely has a unique neural substrate causing Freezing. Any generic treatment is thus usually helpful for some but not for others. In fact, for most Parkinson’s patients, dopamine replacement therapies help prevent blocks, while in rare instances, the same dopaminergic treatment may worsen it in others.
What are the next treatments for Freezing that you believe are most promising for patients?
Dr. Gilat: The complex and heterogeneous nature of this symptom requires a multidisciplinary approach to treatment, including pharmacological (dopaminergic and non-dopaminergic) and behavioral interventions (e.g., physiotherapy, occupational therapy, rehabilitation) that can be tailored to each patient’s clinical and environmental characteristics.
For example, intelligent systems that signal at the right moment may prove more effective than commonly used devices that provide continuous signaling, as intelligent systems provide stimuli only during an imminent Freezing situation, thereby prolonging the effectiveness of stimuli and preventing signal distraction during walking.
Similar need-based strategies could be used for other behavioral techniques and even for deep brain stimulation or non-invasive techniques. Indeed, high-frequency DBS is commonly used in eligible patients, as it often provides substantial relief from cardinal motor symptoms such as rigidity and tremor.
However, at present, these DBS devices stimulate continuously at a single frequency that does not adequately attenuate the paroxysmal symptom of Freezing, which may also benefit from lowering the stimulation frequency.
Thus, new closed-loop DBS systems are being developed to modulate the stimulation frequency based on some kind of external input, such as continuous direct recording of cells at the stimulation site or data from wearable sensors (e.g., accelerometers) that can detect imminent FOG episodes.
Such closed-loop DBS systems could temporarily lower the stimulation frequency during impending Freezing moments and return to the high-frequency setting that is more favorable for improving other symptoms like tremor when the motor block has passed.
DISCOVER GONDOLA AMPS THERAPY FOR TREATING FREEZING OF GAIT
A recent study has shown a significant improvement in gait after 6 weeks of 1-hour cognitive rehabilitation sessions (specifically, developing attentional capacity and information processing activities) twice a week in people with mid-advanced Parkinson’s presenting motor blocks. How might future cognitive interventions improve FOG treatment?
Professor Lewis: There is growing evidence of a link between cognitive deficits and Freezing. Specifically, patients who have this symptom have shown executive deficits in their attention, set-shifting (flexible shifting of attention to relevant information), and motor inhibition.
It is therefore interesting to investigate whether improving the patient’s executive functioning may also improve Freezing. Cognitive training is a non-pharmacological intervention that has been shown to improve executive functioning in Parkinson’s and may also be useful in reducing Freezing of gait.
Our group recently conducted a randomized, placebo-controlled clinical trial to test whether cognitive training targeted at these executive deficits in patients with Freezing would reduce the severity of the symptom compared to an active control group that received cognitive training related to memory and language.
The primary outcome was the difference in the percentage of time spent with Freezing during standardized timed up-and-go tests before and after cognitive training. It is interesting to note that the results revealed that targeted cognitive training reduced the severity of Freezing when patients were on regular dopaminergic medication, but not when they were off medication, compared to the control group.
This finding has strong clinical implications, as patients are primarily on in-home. The finding that cognitive training did not improve Freezing when patients were off medication indicates that this training alone is not sufficient to overcome the severe striatal deficits associated with Freezing.
Are there further areas of research on Freezing that are of particular interest?
Professor Lewis: When Freezing becomes problematic for the patient, its management is already very challenging. Another line of research is therefore aimed at finding the best mechanisms that can predict Freezing to allow for preventive interventions that could prevent the onset of the symptom.
One could imagine that providing targeted cognitive training in the early stages of the disease, when Freezing has not yet developed, could prevent, or at least delay, the onset of motor blocks.
