Movement Disorder in Parkinson's May Be Due to Brain's Rewiring

Parkinson’s is among the most common neurodegenerative and movement disorders that touches the lives of approximately 1% of the population over the age of 60. It is more common among men than women, which suggests apart from genetics, hormonal and environmental factors may play a role. 

Although researchers have suggested various causes, changes in the brain may play a role in the disease's development; however, no one can thoroughly explain the reasons and mechanisms of how this disease develops. It is well known that Parkinson’s is due to the death of dopamine-producing cells in the substantia nigra and other related structures in the brain stem. In later stages, damage to the brain is more widespread.

The role of dopamine has been confirmed in laboratory findings or by various investigations. Levodopa also has proven dopamine's role by increasing the dopamine levels in the brain to improve the symptoms of Parkinson's. 

Parkinson’s disease is primarily characterized by tremors, slowness or rigidity of movements, and as the disease progresses and broader parts of the brain get affected and symptoms of the disease also change. In  the advanced stage, there are cognitive deficits, sleep disturbances, and the person is prone to depression and other disorders.  Although Parkinson’s is a non-fatal disease, it can have a negative impact on a patient's lifespan.

What have we known?

Here is what is known about the disease today, especially the neurological changes associated with the disease. Until now, it is generally accepted that Parkinson's is the result of the loss of neurons in the midbrain, mainly due to the death of dopamine-producing neurons in the structure called substantia nigra. This is why drugs that elevate the levels of dopamine in the midbrain, or surgical methods use to stimulate these areas are useful in decreasing the symptoms.

During the last few decades researchers started looking at Parkinson’s as more of a widespread disease, not just a disorder of motor neurons at some specific location. The presence of so-called Lewy bodies in the small number of surviving neurons in various structures in the brain says something about the common pathways of cell death in Parkinson’s.

Although numerous experiments and scientific studies confirm the role of oxidative stress, inflammation, and proteolytic stress in the development of the disease. Yet, none of the studies can prove which mechanism has more of an important or central role in the development of the disease. This is why it is no surprise that we only have treatment options to slow down the disease and improve the symptoms, but none of the therapy options can reverse the disease or stop it from progressing in the long run.

What we know is just a rough sketch of the problem. We know about the death of cells in the substantia nigra and surrounding structures and more widespread damage to the brain and the benefit of dopamine in disease. However, there is still a lot of mystery surrounding the illness, and we are far from understanding the underlying mechanism. Each study adds to our knowledge and increases our hope of solving the puzzle of the disease development.

New study suggests that movement disorder is due to rewiring

It's now known that whenever something happens in our body, it responds by trying to minimize the damage and compensate for the loss. Studies have also indicated that when the body and brain tries to repair whatever it sees as damage, it can sometimes cause more harm than good from the defensive or compensatory mechanism.

According to these new studies, researchers think that in Parkinson’s a compensatory mechanism is failing to do good. Instead, it is leading to movement disorders. When the cells die in certain motor parts of the brain, the brain tries to rewire the remaining cells to improve the quality of life, but these rewiring instead lead to the movement disorders' characteristics of Parkinson’s.

This latest study is revolutionary in a way that it contradicts many earlier thoughts regarding the disease. Until now, we thought that the brain is really good at compensating the loss of neurons, and nothing wrong can happen during the rewiring process.

Researchers thought that extensive remodeling of the subthalamic nucleus (STN), one of the components of basal ganglia, is somehow related to the kind of symptoms we see in Parkinson’s, including slowness of movements, tremors, and rigidity. The reason behind these views has been the observation of that burst in activity in the cortex (higher brain) that was followed by the abnormal activity in the STN.

Hong-Yuan Chu, PhD, a post doctoral fellow at Bevan lab and his colleagues, expected to see an increase in the cortex to STN transmission with the progress of Parkinson’s, they expected to see the activity of this pathway increase with the death of dopamine-producing cells. However, to their surprise they noticed just opposite, they saw the decline in the cortex to STN pathways. Their initial thought was that they must be doing something wrong. So, they carried out multiple studies using the various methods, and each time the result was the same. This was not consistent with the earlier theories.

As the researchers looked deeper into the issue, they understood that this abnormality was due to the involvement of another structure called the globus pallidus. Changes in the globus pallidus were leaving STN vulnerable to undue the excitement, resulting in more harm than good, causing involuntary movements.

Researchers were able to confirm their findings in the models of the late-stages of Parkinson’s, where prevention of this abnormality resulted in improved symptoms, establishing the link between motor disorder and compensatory mechanisms in Parkinson’s.

The investigators noted that any interruption in these compensatory mechanisms should worsen the symptoms, but they were able to demonstrate just the opposite.

Chu H-Y and his colleagues proposed the new mechanism of motor symptoms related to Parkinson’s. They think that although the brain is successful in compensating for the decline in dopamine in the initial stages, as the disease progresses this compensatory rewiring by the brain may worsen the symptoms.

Like many other studies, it could not explain the entire underlying mechanism of Parkinson’s. These investigations reveal the flaws in our understanding of Parkinson’s. The study only demonstrates the need to stay open-minded, and the importance of continued research in the field.

References

1. Alexander GE. Biology of Parkinson’s disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder. Dialogues Clin Neurosci. 2004;6(3):259-280.
2. Chu H-Y, McIver EL, Kovaleski RF, Atherton JF, Bevan MD. Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons. Neuron. 2017;95(6):1306-1318.e5. doi:10.1016/j.neuron.2017.08.038
3. Braak H, Rüb U, Braak E. [Neuroanatomy of Parkinson disease. Changes in the neuronal cytoskeleton of a few disease-susceptible types of neurons lead to progressive destruction of circumscribed areas in the limbic and motor systems]. Nervenarzt. 2000;71(6):459-469.