The source of essential tremor, a movement disorder that causes involuntary tremor of the hands, arms and head, has been enigmatic, preventing the development of effective treatments for a condition that affects 4% of people over 40.
Now, a new study from the Irving Medical Center at Columbia University and NewYork-Presbyterian suggests that tremors are caused by hyperactive brain waves at the base of the brain, which increases the chance of treating neuromodulation disorder to calm the oscillations
Previous studies have identified changes in brain structure in people with essential tremor, but we did not know how those changes caused tremors. This study determines how those structural changes affect brain activity to boost tremor. “
Sheng-Han Kuo, MD, lead author of the study and assistant professor of neurology at the Vagelos College of Physicians and Surgeons of Columbia University
The study was published online today in Medicine Translational Medicine.
About the essential tremor
Essential tremor is the most common movement disorder in the United States, which affects about 10 million Americans (approximately eight times more people than Parkinson’s disease). The condition causes involuntary and rhythmic tremor, usually in the hands, and is exacerbated during activities such as buttoning a shirt or using utensils. Although the essential tremor does not endanger life, it can seriously affect the quality of life.
Some beta blockers and antiepileptic medications can reduce symptoms, but they have side effects, such as fatigue and shortness of breath. They also do not work very well in patients with essential tremor, which Kuo says is not surprising since the cause of the condition is not well known.
Patients with tremor have excessive brain activity in the cerebellum
The researchers previously identified structural changes in the cerebellum of patients with essential tremor and used a new cerebellar encephalogram (EEG) technique to look for unusual brain waves in this part of the brain.
Among 20 patients with essential tremor examined with cerebellar EEG, the majority had strong oscillations (between 4 and 12 Hz) in the cerebellum that were not found in any of the 20 control subjects. Patients with more severe tremors had stronger oscillations.
Oscillations first encountered in mice
The researchers first discovered cerebellar oscillations in mice that had developed tremors very similar to those observed in patients with essential tremor.
Tremors can be activated and deactivated by stimulating certain neurons in the mouse brain, suppressing and unleashing oscillations alternately. “These results established a causal relationship between brain oscillations and tremor, which cannot be evaluated directly in patients,” says Kuo, who is also an assistant neurologist assistant at the Irving Medical Center of NewYork-Presbyterian / Columbia University.
Excessive oscillations come from additional synapses
In previous studies of postmortem brain tissue from patients with essential tremor, the Columbia team found that patients with essential tremor had an abnormally high number of synapses or connections between two types of nerve cells in the cerebellum of the brain: climbing fibers and cells from Purkinje.
In the current study, again using postmortem brain tissue, researchers found that the formation of these synapses seems to be influenced by a protein called glutamate delta 2 receptor (GluRδ2). “When this protein is underexpressed, the excess synapse that forms between the climbing fibers and the Purkinje cells is not eliminated, resulting in too many neuronal connections,” says Kuo.
When the team reduced the expression of GluRδ2 in mice, the animals developed tremors similar to those observed in humans. Restoring GluRδ2 function suppressed tremor, demonstrating that protein plays a key role in essential tremor.
Potential for new treatments
The study opens several new possibilities for the treatment of essential tremor, says Kuo:
Using cerebellar EEG as a guide, we can use neuromodulation techniques such as tDCS or TMS (transcranial direct current stimulation or transcranial magnetic stimulation) to reduce tremor, or even medications to reduce transmission between climbing fibers and Purkinje cells. “
Kuo is also working to develop medications that increase the expression of GluRδ2 in the brain, which can reduce tremor.
Irving Medical Center of Columbia University
Bread, M-K. et al. (2020) Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to the pathophysiology of tremor. Medicine Translational Medicine. doi.org/10.1126/scitranslmed.aay1769.