Freedom of Movement May Be Misinterpreted as Balance Instability, Parkinson’s Study Suggests

balance instability

Antiparkinsonian medicines may allow patients with mild to moderate Parkinson’s disease to experience freedom of movement, which could be confused with balance issues if measured by traditional postural stability testing, researchers suggest.

Their findings were published in the study, “The influence of dopaminergic medication on balance automaticity in Parkinson’s disease,” in the journal Gait & Posture.

Dopaminergic medications can help control Parkinson’s motor symptoms, but as the disease progresses, patients typically need to gradually increase the treatment dose for maximum benefit. Even after increasing the dose, they might sometimes experience a reappearance or worsening of symptoms (off periods) due to the diminishing effects of the therapy.

It is known that Parkinson’s patients have difficulty performing learned motor skills automatically, a phenomenon referred to as decreased motor automaticity. Automaticity is the ability to perform movements without having to pay attention to the details of the movement, particularly for actions that require low levels of precision or for movements that are frequently made.

Studies also report that the ability to perform two or more tasks at the same time, called dual-tasking, is impaired in Parkinson’s disease.

“Dual-tasking involves performing a primary motor task (e.g., standing) and a secondary task (e.g., conversing) simultaneously and is the primary means of assessing the automaticity of a given motor task,” the researchers wrote.

In theory, if a primary task is automatic, performing another task simultaneously should not interfere with the first one.

Although dopaminergic medication seems to improve dynamic balance (the ability to maintain postural stability while in motion), there is still little evidence on how it influences standing balance (the ability to maintain the body in a fixed posture).

University of Houston researchers set out to evaluate how dopaminergic medication influenced long-duration standing balance with the eyes open or closed while dual-tasking in Parkinson’s disease.

They recruited 16 Parkinson’s patients with mild to moderate disease (four women and 12 men, with a mean age of 67.1 years) for the study.

Before dual-task testing, the participants underwent a minimum 12-hour overnight medication withdrawal, so that researchers could assess patients’ status in an off state.

Single- and dual-task tests were conducted. For dual-task testing, patients had to stand in silence (primary task), both with their eyes open and then with them closed, while listening on headphones to a pre-recorded unfamiliar speech and mentally counting the number of times a specific word occurred (secondary task). This is known as phoneme monitoring. They also had to listen to the details of the story so that they could answer a few questions about it at the end of the testing session.

Under the protocol, participants were asked to perform the following tasks in random order: 1) phoneme monitoring while seated comfortably in a quiet room, 2) single-task standing eyes open, 3) single-task standing eyes closed, 4) dual-task standing eyes open, and 5) dual-task standing eyes closed.

“After the [off] trials were completed, the subjects took their dopaminergic medication as prescribed for their first/morning dose and waited until they achieved a stable ‘on’ feeling (minimum of 45 [minutes]) before commencing the on-medication testing,” the researchers said.

Every trial session was performed once for three minutes, and participants were given at least a minute between sessions to sit down and rest.

Data on motor variables of interest were obtained by the NeuroCom Balance Master, a system that uses a fixed force plate to measure the vertical forces exerted through the patient’s feet to measure the center of gravity position and postural control.

Results revealed that antiparkinsonian medicines significantly increased center of pressure movement. The center of pressure is a point, inside or outside the body, where the resulting vector of all forces (including gravity) acting on the body is considered to act.

Patients’ performance in the secondary task was reduced after they took the medications.

Additionally, having the eyes closed or open significantly increased the patients’ back and forth plus lateral sway velocities and the integrated time to boundary.

In biomechanics, time to boundary estimates the time required for the center of pressure to reach the boundary of the base of support if it were to continue its instantaneous trajectory and velocity. Higher integrated time indicates poorer balance.

Postural sway was also increased during the on state. Scientists often interpret increases in sway velocity and integrated time to boundary as indications of impaired balance; however, the researchers suggest that their findings could indicate an increase in freedom of movement rather than compromised stability.

Importantly, medication did not improve balance automaticity.

“The data did not support a medication-induced improvement in automaticity, as measured by significant medication by task interactions. An alternate interpretation for medication-induced balance changes in PD [Parkinson’s disease] includes an increase in maneuverability without sacrificing stability after taking dopaminergic medication,” the researchers concluded.

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Stem Cell Transplants Could Significantly Improve Parkinson’s Treatment, Study Suggests

stem cell transplant

Cell replacement therapies in which dopamine-producing stem cells are transplanted into Parkinson’s disease patients could improve motor symptoms, reducing or eliminating the need for dopaminergic medicines, a study suggests.

The study, “Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies,” was published in the Journal of Parkinson’s Disease.

Current available treatments to treat Parkinson’s focus on increasing dopamine levels in the brain, which alleviates motor symptoms. However, these treatments’ efficiency declines over time, and they are associated with various side effects.

“We are in desperate need of a better way of helping people with [Parkinson’s disease]. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” Claire Henchcliffe MD, PhD, and Malin Parmar, PhD, co-authors of the study, said in a press release.

A possible long-term treatment for Parkinson’s is transplanting dopamine-producing stem cells into patients’ brains.

“If successful, using stem cells as a source of transplantable dopamine-producing nerve cells could revolutionize care of the [Parkinson’s disease] patient in the future. A single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications,” Henchcliffe and Parmar said.

Previous transplantation studies in Parkinson’s disease used brain cells from aborted embryos. This approach could lead to long-term relief of motor symptoms and can reduce or even stop the need for medication.

However, there are some ethical and scientific issues related to this procedure, including the fact that fetal cells are scarce, their characteristics vary significantly, and some patients can develop side effects, such as dyskinesias (uncontrollable movements).

Using stem cells made in the lab for transplants would allow the production of enough cells to cover the current demand, ensure the number and type of transplanted cells are always the same, that they produce the desired amounts of dopamine, and that the risk rejection is low.

Two possible sources of cells could be used to perform the transplants: embryonic stem cell lines and induced pluripotent stem cells (iPSCs) — cells extracted from a patient’s blood or skin that are treated to become almost any type of cell in the body.

“With several research groups, including our own centers, quickly moving towards testing of stem cell therapies for PD, there is not only a drive to improve what is possible for our patients, but also a realization that our best chance is harmonizing efforts across groups,” said Henchcliffe, who is a neurologist at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center in New York.

Several initiatives, both academic and in the industry, are moving toward testing stem cell therapies to treat Parkinson’s. The first clinical transplantation trials using pluripotent stem cells as donor tissue began in Japan last year.

“There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come,” said Parmar, a professor at the Wallenberg Neuroscience Center and Lund Stem Cell Center at Lund University in Sweden.

New types of transplants focusing on non-motor symptoms could be developed if the initial trials with dopamine-producing cells are successful.

“This approach to brain repair in [Parkinson’s disease] definitely has major potential, and the coming two decades might also see even greater advances in stem cell engineering with stem cells that are tailor-made for specific patients or patient groups,” said Patrik Brundin, MD, PhD, and J. William Langston, MD, editors-in-chief of the Journal of Parkinson’s Disease. “At the same time, there are several biological, practical, and commercial hurdles that need circumventing for this to become a routine therapy.”

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Dopaminergic Medication Lowers Patients’ Sensitivity to Negative Outcomes in Learning, Study Shows

dopaminergic medication

Dopaminergic medication (i.e., levodopa) for Parkinson’s disease appears to bring sensitivity to negative outcomes in learning down to normal levels, a new study shows.

The study, “Dopaminergic medication reduces striatal sensitivity to negative outcomes in Parkinson’s disease,” was published in the journal bioRxiv.

The ability to learn from trial and error plays a major role in decision-making.

Dopamine-producing neurons facilitate learning via trial and error by calculating a value known as the reward prediction error, which refers to the difference between expected and actual reward.

The neurons in the substantia nigra (which are lost in Parkinson’s disease) use bursts and dips of dopamine signaling to relay positive and negative reward prediction error to other parts of the brain, which activates the so-called “Go” and “NoGo” pathways.

When the “Go” pathway is activated, it conveys a signal saying it is OK to proceed with an activity. When the “NoGo” pathway is more active, the action is suppressed.

In Parkinson’s, however, patients lose a substantial portion of dopamine-producing neurons, leading to the depletion of dopamine signaling.

Dopamine medication used by these patients has previously been linked to either behavioral changes during trial-and-error learning or adjustments in approach/avoidance behavior after learning.

But little is known about how dopamine medication leads to differences during learning and how that translates into subsequent changes in approach/avoidance tendencies in patients.

Researchers assessed 24 Parkinson’s patients on and off dopaminergic medication and 24 healthy controls who performed a learning task while undergoing functional magnetic resonance imaging (fMRI).

In the first stage of the experiment — the learning phase — participants gradually learned to make better choices regarding three fixed pairs of stimulus options according to how well they were rewarded (reward feedback).

In the second stage — the transfer stage — participants used their learning phase experience to guide their choices when presented with new combinations of options, without receiving any further feedback.

The decisions during the transfer phase were examined using an approach/avoidance framework.

Additionally, researchers developed a model-based fMRI analysis, which they used to examine medication-related changes in blood-oxygen-level dependent (BOLD) brain signals in response to reward prediction error during learning.

Blood-oxygen-level dependent imaging, or BOLD-contrast imaging, is a method used in functional magnetic resonance imaging (fMRI) to observe different areas of the brain or other organs, which are found to be active at any given time.

Results indicated that, during learning, medication use in Parkinson’s patients reduced an overemphasis on negative outcomes. Hence, patients tended to be less concerned with negative outcomes.

This finding is similar to other studies that show “a [dopamine] medication-driven impairment in behavioral responses relating to negative feedback.”

The shift toward lower sensitivity to negative outcomes in Parkinson’s patients on medication reflects a partially restorative effect of the medication, as sensitivity to negative outcomes became more similar to that observed in healthy controls.

These behavioral adaptations were tied to BOLD changes in the dorsal striatum (the area of the brain directly related to decision-making).

“Medication-induced shifts in negative learning rates were predictive of changes in approach/avoidance choice patterns after learning, and these changes were accompanied by striatal BOLD response alterations,” investigators said.

“These findings highlight dopamine-driven learning differences in PD and provide new insight into how changes in learning impact the transfer of learned value to approach/avoidance responses in novel contexts,” they concluded.

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Brain Training Decreases Severity of Parkinson’s Freezing of Gait, Study Reports

brain training

Brain training reduces the severity and duration of freezing of gait and improves cognition and daytime sleepiness in Parkinson’s patients, a study shows.

The study, “Cognitive training for freezing of gait in Parkinson’s disease: a randomized controlled trial,” appeared in the journal npj Parkinson’s Disease.

Freezing of gait is a symptom of Parkinson’s disease and occurs when patients temporarily feel as if their feet are glued to the floor and hesitate before stepping forward. This often leads to falls and lower quality of life. Studies have shown a connection between freezing of gait and impaired attention and cognitive control.

Researchers in Australia conducted a double-blind trial with Parkinson’s patients who self-reported freezing of gait and had no signs of dementia. Patients were randomly assigned to either cognitive training intervention (20 patients) or an “active control” (18 patients).

Cognitive training consisted of exercises where participants were asked to get up from a chair and walk to a spot marked with a box 5 meters away. Conditions in which patients completed different tasks involving the box were evaluated. Two trials of each condition were completed, one with a left turn and one to the right.

The conditions included: one in which participants walked to the box, turned 180 degrees, and returned to their chair; one where they completed a 540-degree turn in the box before returning to the chair; one in which they shuffled around the box, keeping their inside foot to the outside of the box; and a dual task, where they did the same exercise as the first 180-degree condition, but also completed a cognitive task as they walked, either naming aloud the months backwards or multiples of nine or seven.

Study interventions were conducted twice weekly for seven weeks. Each session took two hours.

The initial 30-45 minutes were common to both groups and included education about a number of topics related to Parkinson’s. Patients undergoing cognitive training then conducted computer tasks targeting processes such as attention, working memory, and brain processing speed. Patients in the active control group completed nonspecific computer tasks.

Investigators primarily evaluated the percentage of time spent frozen during cognitive training, which was analyzed while subjects were both on and off dopaminergic medications. Researchers also assessed several other measures, including mood, well-being, anxiety and depression, sleep quality, and quality of life.

For patients on dopaminergic medication, results showed that those on cognitive training had a significant decrease in the severity of their freezing of gait compared with patients in the active control group. Cognitive training also led to improvements in processing speed and reduced daytime sleepiness.

In contrast, no differences were found when comparing patients not taking regular dopaminergic treatment.

“These results add to the growing body of evidence showing that [cognitive training] is a useful therapeutic technique worthy of continued exploration in [Parkinson’s],” the researchers wrote in the study.

“We believe there is reason to be hopeful for the use of these trials in the future,” Simon Lewis, MD, the study’s senior author and a professor of cognitive neuroscience at the University of Sydney’s Brain and Mind Centre, said in a press release.

He also emphasized the positive feedback from participants and family members, and added that “the results of this pilot study highlight positive trends, and the importance of nonpharmacological trials involving cognitive training has become increasingly clear.”

The researchers also noted the importance of their finding that improvements only occur in patients on dopaminergic medication, “the normal day-day state for patients with Parkinson’s,” said Courtney Walton, PhD, the study’s lead author, who is now at the University of Queensland.

“While more research is needed to better understand and establish these findings, it’s likely that participants in the off- dopaminergic state were too impaired to benefit from any of the potential changes initiated through cognitive training,” Walton said.

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Source: Parkinson's News Today