Researchers at Columbia University Irving Medical Center say that overactive brainwave activity is the underlying cause of essential tremor – a common movement disorder that causes involuntary rhythmic shaking in around 4% of people aged over 40.
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Their study, recently published in the journal Science Translational Medicine, found that people with this movement disorder generate overactive brain waves in the cerebellum, a brain region involved in the coordination of voluntary movement.
The cause of essential tremor has previously been difficult to pinpoint, which has posed challenges in the development of potential treatments. Although researchers have already identified structural changes in the brains of affected individuals, exactly how those changes cause tremor, has remained a mystery.
"Past studies have identified changes in brain structure in people with essential tremor, but we didn't know how those changes caused tremors," Sheng-Han Kuo, assistant Professor of neurology at the University’s Vagelos College of Physicians and Surgeons.
"This study pins down how those structural changes affect brain activity to drive tremor."
Now, the discovery that it is overactive brainwaves that fuel the tremors, raises the possibility that new approaches could be used to diagnose and treat the condition more effectively.
“Understanding the pathophysiology of tremor could help the development of effective therapeutic approaches for treating ET,” writes the team.
More about essential tremor
Essential tremor is the most prevalent movement disorder in the United States, affecting approximately 10 million Americans. The involuntary trembling affects the hands, and is worsened by activities such as tying shoelaces, zipping a coat or handling utensils, which can have a significant impact on day-to-day quality of life.
The condition tends to be more common in people aged over 40 years, with symptoms becoming more severe as a person grows older.
Currently, beta-blockers (blood pressure drugs) and anti-epileptics are used to help reduce symptoms, but these are not always effective, causing adverse side effects such as shortness of breath and fatigue. Kuo says this is not surprising, given that scientists have not yet fully understood the cause of the condition.
Identifying overactive brain waves in the cerebellum
Kuo and the team had already identified structural changes in the cerebellum of essential tremor patients. For the current study, the researchers used a new cerebellar encephalogram (EEG) technique they had developed to examine patterns of brain wave activity in this brain region. Recording electrical signals in the cerebellum are not possible with standard EEG machines.
The team observed some distinct brain wave activity that only occurred in individuals with essential tremor. Strong oscillations of between 4 and 12 Hz were picked up among patients with the condition that were not detected in healthy control subjects. Furthermore, patients who experienced more severe tremors had stronger oscillations.
The oscillations were originally identified in mice
Initially, Kuo and colleagues had detected the abnormal cerebellar brain wave activity in mice that had tremors like those observed in patients with essential tremor. They found that they could stop or start tremors in the animals by stimulating certain neurons in their brains that triggered or suppressed the oscillations.
"These results established a causal relationship between the brain oscillations and tremor, which cannot be directly tested in patients,” says Kuo.
What causes abnormal oscillations?
By studying the postmortem brain tissue of patients with essential tremor, the team had also previously established that these patients had abnormally high numbers of synapses connecting nerve cells in the cerebellum called climbing fibers and Purkinje cells (PC and FC).
In the current study, the team used postmortem brain tissue again to study the formation of these synapses, which they found seemed to be influenced by a protein called glutamate receptor delta 2 (GluRδ2).
When GluRδ2 is underexpressed, any excess synapses formed between climbing fibers and Purkinje cells are not eliminated, which results in too many neural connections, explains Kuo.
The case for GluRδ2 insufficiency as a contributor to essential tremor was made even stronger when the team studied mice engineered to have reduced expression of the receptor. The animals developed tremors that were similar to those observed in humans with the condition. The tremors also became more severe as the animals aged.
Furthermore, when the team corrected the GluRδ2 deficiency by restoring the protein’s function, tremor symptoms improved, indicating that GluRδ2 plays a key role in essential tremor.
Potential new treatments
The researchers say the findings could pave the way for potential new treatments:
“Our findings identify a pathophysiologic contribution to tremor at molecular (GluRd2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET [essential tremor],” writes the team.
"Using cerebellar EEG as a guide, we may be able to use neuromodulation techniques such as tDCS or TMS (transcranial direct-current stimulation or transcranial magnetic stimulation) to reduce tremor or even drugs to reduce transmission between the climbing fibers and Purkinje cells,” says Kuo.
The team also plans to apply their results to future studies testing the effectiveness of drugs at reducing tremors and Kuo is already trying to develop agents that increase GluRδ2 expression in the brain.
Overactive brain waves trigger essential tremor. Medical Express 2020. Available at: https://medicalxpress.com/news/2020-01-overactive-brain-trigger-essential-tremor.html
New Study Finds Overactive Brain Waves Cause a Common Movement Disorder Called Essential Tremor. Discover 2020. Megan Schmidt. Available at: https://www.discovermagazine.com/mind/new-study-says-essential-tremor-is-caused-by-overactive-brain-waves
Pan M, et al. Cerebellar oscillations are driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology. Sci. Transl. Med. 12, eaay1769 (2020).