More than half of the patients with Parkinson's disease suffer from Freezing of the march. The symptoms of the Freezing vary, some have an alternating tremor of the legs or a reduction in stride length to a shuffling of the feet, while other patients describe a sensation of motor blockage, as if the feet as “stuck to the floor” while the upper body continues to move.
l Freezing can be triggered by various factors, situations (e.g., cognitive, emotional) and environments, such as double tasking (i.e., performing two actions at the same time, e.g., talking and walking), approaching or passing through a narrow passage or doorway, turning around, being in a crowd, having many distractions, approaching the end point (such as couch), 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 the Freezing of the march, such as traditional oral dopaminergic drugs and deep brain stimulation (DBS), are at best only partially effective in many patients.
Here is an interview with two of the authors of the review, Moran Gilat, PhD, postdoctoral researcher in 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, about 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 been shown to be one of the most debilitating features of Parkinson's disease.
So only in the last decade has there been an increase in research studies regarding its neuronal basis and the limited effectiveness of existing treatments (such as dopamine replacement therapies).
In addition, the Freezing is more common in the advanced stages of the Parkinson's disease, when both substance nigra and substance extranigra pathologies spread and affect a multitude of neuronal circuits that play a role in the Freezing.
However, the spread of pathology and subsequent degeneration are different among patients and difficult to delineate, making it difficult to tailor pharmacological interventions to each patient's neural needs.
At this late 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 nonpharmacological interventions to each patient's characteristics affecting the severity of Freezing of the March.
Is Freezing more difficult to treat in some patients than others?
Professor Lewis: Freezing becomes increasingly difficult to treat, especially when it becomes resistant to dopamine in the advanced stages of the disease. As Parkinson's disease spreads over time, more and more areas of the brain, which have been shown to play a role in the onset of Freezing, are affected.
For example, as the disease progresses, patients in particular develop cognitive deficits, especially in their executive functioning, implying frontal cortical dysfunction.
These cognitive deficits probably result from extranigral degeneration of cholinergic and noradrenergic neurons that perform an important task in these frontal areas of the brain. Since executive dysfunction is involved in the etiology of Freezing, it becomes important to manage these deficits to counteract cognitive decline and also prevent motor blocks.
However, as mentioned earlier, the spread of the disease and subsequent degeneration are different among patients, making difficult to adapt drug treatments and test the effects of new drugs in future clinical trials, as these require large groups of patients to have good statistics of the results.
However, since Freezing in patients is caused by different neuronal deficits, it will be very unlikely that one therapy will have a positive effect on all, as not all patients will be sensitive to the therapy, depending on their neuronal deficits.
What makes march freezing so difficult to treat? How does disease heterogeneity/interindividual variability come into play?
Dr Gilat: Freezing of walking in Parkinson's is a highly heterogeneous symptom, as illustrated by the variety of situations that trigger motor blocks to different degrees for each patient.
That is, some patients often get stuck when walking through doors or when trying to turn in place, while others might get stuck more commonly when performing a cognitive task, such as talking, while walking or when feeling anxious.
This indicates that each patient probably has a unique neural substrate that causes Freezing. Any generic treatment is therefore usually helpful for some, but not for others. In fact, for most Parkinson's patients, dopamine replacement therapies help prevent blockages, while on rare occasions, dopaminergic treatment itself may worsen it in others.
What upcoming Freezing treatments do you think hold the most promise 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, smart systems that give a signal at the right time can be found to be more effective than commonly used devices that give a continuous signal, as smart systems give stimuli only during an impending Freezing situation, thus prolonging the effectiveness of the stimuli and preventing distracting signals during a walk.
Similar strategies on need could be used for other behavioral techniques and also for deep or noninvasive brain stimulation techniques. Indeed, high-frequency DBS is commonly used in eligible patients because it often offers substantial relief from cardinal motor symptoms such as rigidity and tremor.
However, at present, these DBS devices continuously stimulate on a single frequency that does not satisfactorily attenuate the paroxysmal symptom of Freezing, which may also benefit from lowering the stimulation frequency.
Thus, new closed-loop DBS systems are being developed that can modulate the frequency of stimulation based on some kind of external input, such as direct continuous recording of cells at the stimulation site or data from wearable sensors (e.g., accelerometers) that can detect impending FOG episodes.
Such closed-loop DBS systems might temporarily lower the frequency of stimulation during times of impending Freezing and return to the high-frequency setting that is more favorable for improving other symptoms such as tremor during periods when the motor block has passed.
DISCOVER GONDOLA AMPS THE THERAPY FOR TREATING GEAR FREEZING
A recent study demonstrated significant improvement in walking after 6 weeks of 1-hour cognitive rehabilitation sessions (specifically, development of attention skills and information-processing activities) twice a week in people with mid-to-late-stage Parkinson's who had motor blocks. How could future cognitive interventions improve the treatment of eye fog?
Professor Lewis: There is growing evidence of a link between cognitive deficits and Freezing. Specifically, patients with this symptom showed executive deficits in their attention, set-shifting (flexible shifting of attention to sensed 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 nonpharmacological intervention that has been shown to improve executive functioning in Parkinson's and may prove useful in reducing Freezing of walking as well.
Our group recently conducted a randomized, placebo-controlled clinical trial to test whether cognitive training directed at these executive deficits in Freezing patients would reduce symptom severity compared with an active control group that had received cognitive training related to memory and language.
The first result was the difference in the percentage of time spent with Freezing during up-and-go time-standardized tests before and after cognitive training. Interestingly, 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 with the control group.
This finding has strong clinical implications, as patients are mainly in the on phase at 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 additional areas of research on Freezing that are of particular interest?
Professor Lewis: When Freezing becomes problematic for the patient, its management is already very difficult. Another line of research is, therefore, aimed at Finding the best mechanisms that can predict Freezing to allow preventive interventions that could prevent symptom onset.
One could imagine that providing targeted cognitive training in the early stages of the disease, when Freezing is not yet developed, could prevent, or at least postpone, the onset of motor blocks.
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