Subthalamic Deep Brain Stimulation Parameters for Gait Impairment in Parkinson’s Disease Patients

Abstract

Parkinson’s disease is an age-associated neurodegenerative disease that affects about 572/100,000 North Americans ages 45 and older [11]. Progression of the disease can be crushing for both patients and their loved ones, with no permanent cure in our current medical arsenal [13]. Gait (manner of walking) impairment is a particularly debilitating feature of Parkinson’s disease, which can range from arm swing asymmetry to freezing and difficulties with balance. This often contributes to movement decline as the disease progresses. Typical treatment of symptoms includes dopaminergic medications, such as Levodopa; however, some patients cannot tolerate the side effects or do not experience symptom reduction. In these cases, more invasive treatments must be considered by treating clinicians. This review aims to evaluate the current evidence for proper treatment parameters for gait impairment, with particular focus on subthalamic deep brain stimulation—an invasive yet effective treatment for the motor symptoms of Parkinson’s disease.

Introduction

Parkinson’s disease (PD) symptoms are typically divided into three main categories: motor (e.g., rigidity, tremor, and gait impairment), cognitive (e.g., executive dysfunction, impaired processing speed, and memory loss), and behavioral (e.g., visual/auditory hallucinations, apraxia of speech, disinhibition, and apathy) [10]. The prevailing theory of the disease suggests that a dysfunction of dopamine transmission is a contributing factor; specifically, a degeneration of dopaminergic neurons [9]. Current treatments are unable to completely halt the progression of PD, though dopaminergic drugs such as Levodopa can effectively ease motor symptoms [9]. However, dopaminergic drugs become less effective as the disease progresses and the body’s ability to store dopamine worsens [9]. Another effective, yet unconventional approach is subthalamic deep brain stimulation (STN-DBS). This technique requires the surgical implantation of electrodes in the subthalamic area of the brain, which are connected to a neurostimulator to regulate brain activity via electrical pulses at varying frequencies [5]. Current literature debates whether low- or high-frequency stimulation is more effective for long-term relief, taking into consideration whether STN-DBS is used in addition to dopaminergic medications [2, 3, 8].
The majority of researchers have found that low-frequency stimulation results in a short-term improvement in gait, followed by long-term deterioration. It should be noted, however, that a small percentage of studies find both short-term and long-term improvement in gait after low-frequency stimulation, as well as improvements after high-frequency stimulation. This review will focus on the effects of STN-DBS on gait impairment in Parkinson’s disease, with special attention given to low- vs. high-frequency stimulation, medication vs. no medication, and short- and long-term effects.

Low Frequency

Promising results for gait improvement have come from the use of low-frequency stimulation. Using 60-Hz stimulation, the authors of one study found a significant improvement in postural stability compared to high-frequency stimulation [4]; however, a relatively small sample size was used (n=14), so caution should be taken before drawing conclusions. It should also be noted that some patients were unable to tolerate the lower frequency as it triggered pre-operative resting tremor initially treated with high-frequency stimulation [4]. This is an important factor for clinicians to consider when creating a treatment plan for their patients.
A particularly unique study used subthalamic coordinated reset deep brain stimulation (ST-CR-DBS) on nonhuman primates (NHP)-rendered-parkinsonian via intracarotid and intramuscular neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection [1]. ST-CR-DBS is a relatively new treatment, using low levels of burst stimulation to target specific motor impairments. With the potential to customize stimulation based on individual patients’ needs, ST-CR-DBS has been shown to improve gait in NHP-rendered-parkinsonian using 21 Hz stimulation [1]. While results are indeed promising, they are still preliminary—the sample size is small (n=3), and the results found in NHP may not be generalizable to the human PD population. The study was also done in a closed laboratory, lending itself to little external validity. Follow-up with a larger human cohort will be useful in determining the reliability and validity of this potential treatment.

High Frequency

While there is agreement between studies on the effectiveness of low-frequency stimulation for gait dysfunction, there is also compelling evidence showing improvements after the use of high frequency. Using high-frequency stimulation (120 Hz), researchers found an increase in step length and double stance phase (a phase in the gait cycle where both feet are on the ground), and improved cadence (walking tempo) in patients with advanced PD compared to a preoperative baseline [7]. This study was done in a laboratory, however, and would benefit from a follow-up study in a real-life setting for more compelling external validity. Although more research needs to be done to evaluate the benefits of high-frequency stimulation, another study shows promising improvements in gait using high frequency even when patients were not on antiparkinsonian medication [8].

Medication vs. No Medication

Another important factor to take into consideration is the efficacy of dopaminergic medication in conjunction with STN-DBS. One study found STN-DBS to be useful when used in addition to antiparkinsonian medication [3]. However, there are a few limitations with this study: the sample size was relatively small (n=25), there was no preoperative measurement, and the follow-up duration between patients was admitted by the authors to be variable [3]. Conditions were not counterbalanced and only four patients received low-frequency stimulation, so comparison between low- and high-frequency stimulation was not possible.
Conversely, some studies have found STN-DBS to be effective on its own [8], perhaps more than medication alone [7]. One such study used a paradigm in which patients were given the Unified Parkinson’s Disease Rating Scale (a scale used to determine functional impairments in PD patients) during 4 different conditions: medication ON preoperatively, medication OFF preoperatively, medication OFF/stimulation ON postoperatively, and medication ON/stimulation OFF postoperatively. The results of this study found a notable improvement in gait during the medication OFF/stimulation ON state at a 5-year postoperative follow up [8]. This experimental design was rigorous and had tight controls; thus, the claims of this study are particularly strong.
Compounding the efficacy of low- vs. high-frequency stimulation, special consideration should be given to the use of dopaminergic medication and its efficacy for each individual patient. Every patient has different needs, so a customized approach may be superior to a blanketed approach when designing a treatment plan. Overall, more research should be done to build convincing evidence for the individualized use or discontinuation of dopaminergic medication when treating patients using STN-DBS.

Long- vs. short-term improvement

A short-term improvement in symptoms after STN-DBS treatment is observed in multiple studies regardless of stimulation frequency [3]. While this seems promising at first, others have found an initial improvement in gait, with a significant decline over time [2]. Some studies attribute this progressive deterioration to the use of high-frequency stimulation for PD patients; this hypothesis is well supported as this deterioration seems to improve once lower-stimulation frequency is used [2]. Although some studies find high-frequency stimulation to be unsustainable long-term (>5 years), another study observed a long-term gait improvement after 130 Hz stimulation, even without the use of medication [8].
With the relative lack of current research, causal relationships for long- vs. short-term improvement cannot yet be made. There is conflicting evidence on what contributes to long-term deterioration; some studies claim it is induced by high-frequency stimulation. More work should be done to disentangle these two opposing views in order to come to a consensus on long-term expectations for PD patients undergoing STN-DBS treatment with or without dopaminergic medications. 

Conclusion

Much of the current literature agrees that low-frequency stimulation shows promising results for the treatment of gait impairment in PD patients; however, more research is necessary to reveal the potential for long-term improvement. It is also unclear when high-frequency stimulation should be considered over low frequency for a particular patient. Another important factor to consider when treating patients is whether to use dopaminergic medication in addition to STN-DBS, so long as it is effective and well-tolerated by the patient.

With an increasing elderly population, it is more imperative than ever to find effective treatments for patients with PD. Equipped with the proper guidelines, clinicians will be able to tailor treatment plans to each individual patient’s needs more effectively—for patients, this can lead to an easing of symptoms and a more tolerable transition to the late stages of disease.

About the Author: Desiree Lano

Desiree Lano is a fifth-year Psychology major with an emphasis in biology, minoring in Neuroscience. For as long as she can remember, she has been fascinated with human behavior. As she furthered her education, she became intrigued with the biological underpinnings of what she saw around her. Her main research interest is the neurobiology of schizophrenia, and she hopes to dedicate her career to contributing to the growing body of knowledge in order to help those suffering with the disorder and eventually reduce public stigma. After graduation she plans on pursuing a PhD in Neuroscience, specializing in cellular and molecular neuroscience. In her free time she enjoys playing video games, reading, drawing, and spending time with her beloved dog and boyfriend.

Author’s Note

When I learned that we were going to write a literature review in my Writing in Science class, I was ecstatic to have the opportunity to learn how to be an effective science writer. I have long had a passion for brain science, and it is not often that an undergraduate gets the chance to dig into such a comprehensive research endeavor. We have all seen the tragic manifestations of Parkinson’s disease, but not many people know about this exciting technique. Deep brain stimulation is a perfect example of the wonders of modern biomedical science and what we have yet to achieve—this is just the beginning!

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