Antiparkinsonian Medication Improves Learned Movement Production by Boosting Neuronal Connectivity, Study Finds

Antiparkinsonian Medication

Dopaminergic therapy may ease difficulties with gesturing and using tools in people with Parkinson’s disease by improving brain connectivity between the cognitive and motor regions, a study has found.

The study results, “Dopaminergic modulation of the praxis network in Parkinson’s disease,” were published in NeuroImage: Clinical.

Parkinson’s patients often have trouble performing skilled or learned movements that are crucial for daily living. Praxis is what scientists call this kind of cognitively directed motor action, while apraxia, generally speaking, refers to the difficulty itself, i.e., any disorder of learned movement.

“Although the neuronal basis of praxis functions has been comprehensively investigated in healthy individuals, functional imaging studies targeting these abilities including their impairments in clinical samples are still rare,” the researchers wrote.

Medical University of Vienna researchers studied the functional connectivity of the praxis network in individuals with mild-to-moderate Parkinson’s and at an increased risk for apraxia. They also investigated the influence of dopaminergic therapy on praxis function-related brain network.

For this purpose, a total of 13 Parkinson’s patients (seven men and six women, mean age of 60.23 years) and 13 healthy controls (seven men and 6 women; mean age of 56.77 years) underwent functional magnetic resonance imaging (MRI) and apraxia assessments.

Functional MRI measures the small changes in blood flow that occur with brain activity in response to stimuli or actions.

In the Parkinson’s group, all tests were performed twice: once with individually optimized dopaminergic medication (“on” state) and once without (“off” state).

None of the participants had trouble imitating gestures upon demonstration of object use, and none of the Parkinson’s patients showed apraxia-like symptoms. However, patients in the off period (without optimized symptom control by medication) performed significantly poorer in praxis assessments than controls.

Regarding functioning of the praxis-related brain network, patients in both states (on and off) displayed higher global efficiency than healthy individuals. Further analysis revealed that most of the communication within the network relayed to the bilateral supramarginal gyri, a portion of the brain that is thought to be involved in language perception and processing.

In addition, patients with optimized dopaminergic medication showed higher connectivity between praxis and motor areas, particularly between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas, in comparison to subjects in the “off” state.

This improved communication “might facilitate the propagation of long-term representations of object-related actions to motor execution areas,” thus enabling the correct execution of the wanted movement.

The praxis network was confined to the left-brain hemisphere in the control sample, while in patients “off” therapy, but not in “on” individuals, the  network expanded to the right hemisphere.

Importantly, antiparkinsonian treatment seemed to normalize patients’ learned movement skills and related network connectivity, suggesting such therapy may support higher-order cognitive motor functions, at least in early stages of this neurodegenerative disorder.

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Dopamine May Prevent Movement Impairment in Parkinson’s Patients, Study Suggests

dopamine, movement impairments

Levodopa treatment can prevent movement impairment in patients with Parkinson’s disease by increasing overall sensory attenuation, or the ability to fine-tune information received from the senses before a motor action is performed, a study suggests.

Based on these findings, researchers suggest that dopamine, which increases as a result of levodopa treatment, may be important for regulating brain activity to effectively integrate predictions of action with sensory information — a process required for the control of voluntary movements.

“This may provide a common framework for understanding the role of dopamine in perceptual, cognitive, and motor function,” they wrote.

The study, “Sensory attenuation in Parkinson’s disease is related to disease severity and dopamine dose,” was published at the journal Scientific Reports.

Parkinson’s disease is often characterized by slower movements, which are associated with the impaired ability of patients to plan, initiate, and execute voluntary movements. However, the underlying mechanisms that promote these deficits are still not very well understood.

Researchers evaluated the sensorial and motor response of 18 patients with idiopathic Parkinson’s disease and 175 age and gender-matched healthy volunteers used as controls. All Parkinson’s patients were receiving treatment with levodopa, one of the main therapies used to increase the levels of dopamine.

To quantify participants’ sensorimotor response, researchers used the force matching task, in which a torque motor applies one of four force levels through a lever to the left index finger. Participants are then asked to match the force they just sensed either by pressing the lever with their right index finger (direct condition), or by sliding a linear potentiometer that controls the torque motor (slider condition).

In response to this test, people often apply a stronger force when exposed to the direct condition, while they tend to use a more accurately matched force in the slider condition. The overcompensation of forces that occur in the direct condition has been associated with the integrity of the fronto-striatal network — an area of the brain strongly affected by dopamine deficits in Parkinson’s disease.

Task results revealed that Parkinson’s patients had less sensitivity than controls. Still, the overall force response to matching the applied motor force was similar between patients and controls.

Further analysis showed that overall sensory attenuation was negatively related to Parkinson’s motor severity, but positively linked to individual patient dopamine levels, as measured by levodopa dose equivalent.

In general, patients who were taking higher levodopa doses were also the ones showing greater overcompensation on the direct condition of the task.

“These results support the hypothesis that dopamine alleviates disorders of movement in Parkinson’s disease by restoring the precision and hence the typical reliance on sensorimotor predictions,” the researchers wrote.

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Sensor-Based Gait Analysis Can Enhance Individualized Evaluation of Parkinson’s Patients, Study Suggests

sensor-based gait assessment

Use of sensor-based methods to evaluate gait can improve individual assessments of Parkinson’s disease patients who are undergoing dopaminergic treatment, researchers suggest.

The study with that finding, “Sensor-based gait analysis of individualized improvement during apomorphine titration in Parkinson’s disease,” was published in the Journal of Neurology.

Gait impairment as a consequence of Parkinson’s disease progression can drastically reduce patients’ quality of life. However, available strategies to evaluate gait alterations for individual patient care are still limited.

More recently, the development of mobile sensor-based gait analysis methods has enabled the objective assessment of gait deficits in Parkinson’s patients. Still, the applicability and effectiveness as an individualized evaluation approach has not been established.

A team led by researchers at FAU Erlangen-Nürnberg in Germany compared gait outcomes measured with standard and sensor-based methods in Parkinson’s patients undergoing dopamine replacement therapy.

The study enrolled 13 patients who had mean disease duration of about 15 years and were receiving a mean levodopa equivalent daily dose of 1,077 mg.

All participants started treatment with Apokyn (apomorphine) according to standard protocol, by injecting a defined dose subcutaneously (under the skin) every 15 minutes until achieving the best motor response. Apokyn is an injectable agent usually used to restore body movement control between doses of levodopa, during “off” periods — periods when medication wears off and symptoms reappear.

To track gait movement, researchers used sensors (3D-acceerometers and 3D-gyroscopes) attached to the shoes that could detect small changes in movement orientation and speed. These sensors measure parameters such as rotation and dynamic acceleration resulting from motion, shock or vibration, and can measure tremor in these patients.

After treatment with Apokyn, patients showed a significant improvement in gait movement, as shown by increase in certain gait parameters, including stride speed and length, maximum toe clearance, gait velocity, swing time, heel strike angle, and toe-off angle.

To better evaluate the potential of sensor-based gait analysis to perform individualized evaluations, researchers compared the data obtain between Apokyn administrations within in each patient.

This strategy allowed them to confirm that sensor-based results could effectively measure small gait differences resulting from Apokyn dosages. It could discriminate significant improvements in stride speed, length, and time, and maximum toe clearance between two sequential administrations, as well as detect when no additional improvements were achieved with higher doses.

To validate these findings, researchers compared the sensor-based data with motor scores collected with the standard measure Unified Parkinson Disease Rating Scale (UPDRS) (a 50-question assessment of both motor and non-motor symptoms associated with Parkinson’s).

Improvement in gait parameters (obtained using sensor-based gait analysis) between Apokyn injections reflected improvement in patients’ overall motor performance as measured by the UPDRS, in particular in items related to postural stability and gait.

“[S]ensor-based gait analysis provides objective target outcome measure of gait performance, reflecting apomorphine-induced improvement of motor performance in [Parkinson’s disease],” researchers wrote.

“We show that using instrumented gait analysis to measure individual changes in gait parameters … may be a powerful assessment strategy for routine clinical care in individual [Parkinson’s disease] patients,” they concluded.

However, the authors caution that additional studies in larger groups of patients are still warranted to further validate the applicability and implementation of sensor-based gait analysis as an objective and individualized diagnostic tool for real-life healthcare.

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Parkinson’s Patients with Tendency to Fall Control Balance Differently than Non-Fallers, Study Suggests

Parkinson's fall risk

Parkinson’s disease patients who have a tendency to fall use different strategies to control their balance than those who do not fall, according to a recent study.

The study, “Fallers with Parkinson’s disease exhibit restrictive trunk control during walking,” was published in Gait and Posture.

Due to Parkinson’s-related motor imbalance, falls are a common consequence of the disease, and the risk of falling increases as patients get older and as the disease progresses.

Parkinson’s patients are twice as likely to fall than older adults living independently, and are also nine times more likely to have recurrent falls.

Observational studies suggest these patients underestimate the amount of work necessary for their muscles to produce a certain movement. They compensate for this lack of motor and perceptual ability by adopting distinct postural strategies to keep their balance during both static and dynamic movements.

Static measures of posture control can distinguish Parkinson’s patients from healthy older adults, but not Parkinson’s fallers from non-fallers.

“A better understanding of the relationship between falls and static and dynamic movements may provide further insight into falls-risk assessment in this clinical population,” the researchers said.

To study this, researchers at the University of Ottawa in Canada conducted a study that recruited 25 Parkinson’s patients and 17 healthy older adults used as controls.

They analyzed postural differences between Parkinson’s fallers and non-fallers, based on the self-reported occurrence of falls in the previous three months, and between healthy controls.

Motor disability was measured using the Unified Parkinson’s Disease Rating Scale III, cognitive impairment by the Montreal Cognitive Assessment, and freezing of gait by the Freezing of Gait questionnaire.

Participants were given static and dynamic motor tasks, consisting of one quiet standing condition and one walking condition (walking 15 meters while looking straight ahead).

Both tasks were presented twice and lasted for 30 seconds. Testing was performed while patients were optimally medicated with dopaminergic therapies.

The standing test was sensitive enough to distinguish between Parkinson’s patients and healthy controls, but not between fallers and non-fallers with Parkinson’s disease. However, static tasks were less sensitive in differentiating between fallers and non-fallers with Parkinson’s disease and healthy older adults than dynamic tasks.

Fallers had difficulty controlling their upper body (torso) when walking, compared with non-fallers and the control group. This was also true for individuals with Parkinson’s disease versus older healthy adults.

Importantly, falling was associated with static and dynamic postural control in Parkinson’s patients, with fallers and non-fallers adopting different postural strategies to regulate balance.

“Overall, this study provides useful information for falls-risk assessments as well as for developing fall prevention program specific to fallers and non-fallers with PD,” the researchers concluded.

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Scientists Unraveling How Movement is Translated Into Desired Action

mice movement brain

The findings of a Harvard University study are furthering understanding of the mechanisms involved in movement disorders and may open new therapeutic opportunities to treat Parkinson’s disease.

The mouse study, “The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection,” was published in the journal Cell.

The brain relies on the balanced activity of two nerve cell populations located in a specific region of the brain — the striatum — to achieve accurate control of body movement. The striatum functions as the coordinating center for motor and action planning. In Parkinson’s disease, striatum nerve cells are those most affected, which partly explains the motor symptoms that characterize the disease.

A previous study identified two groups of nerve cells in the striatum that have opposing activities to control key aspects of movement; those are called direct pathway and indirect pathway neurons.

While direct pathway cells select actions and can trigger movement, the activation of indirect pathway cells works as a stop signal, inhibiting unwanted behaviors. However, some studies suggest both pathways are activated at the same time.

“That didn’t make sense based on what we’ve long thought each pathway did,” the study’s lead author Jeffrey Markowitz, said in a press release.

To evaluate the dynamic activity of both cell populations, Harvard Medical School researchers used a technology called MoSeq (short for motion sequencing) developed by study’s senior author Sandeep Robert Datta. This technology films three-dimensional movements of the mice and uses machine learning to analyze the movements into basic patterns lasting only a few hundred milliseconds apiece. The researchers named those ultra-fast movements “syllables.”

Mice were genetically engineered to display different glowing colors in direct and indirect pathway neurons upon activation, allowing researchers to accurately analyze the simultaneous activity of both cell populations as mice performed several actions.

When mice changed their behavior — from running to stopping, for example — the activity of both pathways increased, which is in agreement with data from previous studies. But when they looked at the syllables identified by the MoSeq system, they found the pattern of activity of both pathways was not the same.

Instead, direct or indirect pathway cells dominated some particular syllables. The association between the type of cell that was activated and syllables was so pronounced that the team could effectively identify syllables based on the pathway activity alone.

To further characterize the role of these cells, the team induced brain injuries in the mice, targeting only the striatum. After a week of recovery, they re-analyzed animals’ behavior and compared them with that of healthy animals.

Mice with brain lesions in this specific area also were able to perform normal syllables, such as sniffing, running, rearing, and turning. However, their brains were unable to sequence these movements correctly.

“… behavioral syllables are associated with characteristic and pathway-specific neural dynamics. These dynamics represent key 2D and 3D movement parameters … the striatum plays a key role in choosing which … behavioral syllable to express at any given moment,” researchers wrote.

“This underscores the importance of order in piecing movements together toward a desired outcome,” Datta said. “Even if you’re able to move your body correctly, if you can’t put actions in the correct order, it’s hard to do even the most basic of things.”

The researchers believe that with additional studies and improved technology it will be possible not only  to replicate these results, but expand this reported relationship between syllables and neural activity to other parts of the brain that control movement.

In addition, these findings may help promote the development of new treatments for Parkinson’s disease and other neurodegenerative disorders in which basic movements become extremely difficult as disease progresses.

“We hope that future work emanating from these findings would address more specifically what exactly happens in these cell types when neurodegenerative disorders rob people’s brains of their ability to generate actions and action sequences.” Datta said. “We believe our observations set the stage for both unraveling how movement gets translated into desired action, and propel us forward in our ability to understand and, eventually, treat devastating neurodegenerative disorders where this process goes awry,” he added.

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New Insights on Brain-Muscle Wiring and Movement Control May Aid in Parkinson’s Research

Brain-muscle wiring study

Unexpected external stimulus, such as a sound or visual cue, can act as an alarm for the brain to detect a dangerous situation, according to a study that has implications for Parkinson’s disease.

These sensory triggers were found to promote an inhibitory signal from the brain to quickly stop muscles from reacting, providing new insights on how the brain and muscles interact to control movement.

The University of Iowa  researchers studied how people stopped an action. They found that when participants heard an unexpected sound, they stopped an action more often than when they heard no sound at all.

These findings may help researchers understand how to enhance brain-muscle communication as a strategy to treat patients with motor-control disorders, such as Parkinson’s disease and attention deficit hyperactivity disorder (ADHD).

The study, “Perceptual Surprise Improves Action Stopping by Nonselectively Suppressing Motor Activity via a Neural Mechanism for Motor Inhibition,” appeared in The Journal of Neurosciences.

Sixteen healthy volunteers had to perform a simple Go or No Go task and were either exposed or not to warning sounds. During the experiments, brain activity was measured, as well as muscle response.

Researchers observed that when participants were exposed to unexpected warning signals, they would stop their action more often than when they heard no sound at all (80% vs 65%).

This improved stopping action response was found to be accompanied by increased brain activity that was associated with increased stop signals sent to the muscles.

A similar inhibitory response was also reported when participants were trained to expect the warning sounds. Even though they were expecting the warning sound, the brain still responded in a protective way by blocking their action.

“It seems like the brain’s communication with the motor system is so hard-wired, and this ability to stop an action is so innate, that even repeated practice won’t really alter it,” Jan Wessel, assistant professor in the department of psychological and brain sciences at UI and senior author of the study, said in a university press release. “Therefore, finding other avenues to trigger the brain’s rapid stopping and improve stopping outcomes could be of great potential.”

This type of inhibitory response is not limited to sounds but to any unexpected event, Wessel said. “The hypothesis is that an unexpected visual event, or an unexpected vibration on your skin, would have the same effect. It’s just the fact that something happened that was unanticipated,” he added.

Experimental data revealed that the communication between the brain and the motor system is almost instantaneous, happening in fractions of a second. “Our brain has evolved to do this. The human brain is adapted for survival, and I think that’s why these systems are hard-wired with one another,” Wessel said.

Collectively, these findings suggest that the brain and the muscles are tightly linked to manage surprise response and movement control. This opens new research options for reactive motor control in situations of impaired response, the researchers said.

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