Essential tremor is the most common movement disorder in the United States, affecting about 10 million Americans (approximately eight times as many people as Parkinson’s disease). The condition causes involuntary, rhythmic trembling, usually in the hands, and is exacerbated during such activities as buttoning a shirt or using utensils. Although essential tremor is not life-threatening, it can severely impact 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. Some beta blockers and anti-epileptic drugs can reduce symptoms, but they carry side effects, such as fatigue and shortness of breath. They also don’t work very well in essential tremor patients, which isn’t surprising since the cause of the condition hasn’t been well understood. The source of essential tremor–a movement disorder that causes involuntary trembling of the hands, arms, and head–has been enigmatic, impeding the development of effective treatments for a condition that affects 4% of people over 40. Now a new study from Columbia University Irving Medical Center and NewYork-Presbyterian suggests the tremors are caused by overactive brain waves at the base of the brain, raising the possibility of treating the disorder with neuromodulation.
In previous studies of postmortem brain tissue from essential tremor patients, the Columbia team discovered that patients with essential tremor had an abnormally high number of synapses, or connections, between two types of nerve cells in the brain’s cerebellum–climbing fibers and Purkinje cells. The researchers have previously identified structural changes in the cerebellum of essential tremor patients and used a new cerebellar encephalogram (EEG) technique to search for unusual brain waves in this part of the brain. Among 20 essential tremor patients examined with cerebellar EEG, most 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. The researchers first discovered the cerebellar oscillations in mice that had developed tremors closely resembling those seen in essential tremor patients. The tremors could be turned on and off by stimulating certain neurons in the mouse brain, alternately suppressing and unleashing the oscillations. These results established a causal relationship between the brain oscillations and tremor, which cannot be directly tested in patients.
In the current study, again using postmortem brain tissue, the researchers found that the formation of these synapses appears to be influenced by a protein called glutamate receptor delta 2 (GluRδ2). When this protein is underexpressed, any excess synapses that form between climbing fibers and Purkinje cells are not eliminated, resulting in too many neuronal connections. Glutamate GluR δ2 receptor is an orphan receptor since when expressed alone or with other glutamate receptors, GluRdelta2 does not form functional glutamate-gated ion channels nor does it bind to glutamate analogs. Moreover, application of an antibody specific for GluRdelta2’s extracellular N-terminal region abrogated synaptic plasticity, indicating that this receptoris needed for neuronal remodeling. Moreover, again i the cerebellum it interact with proteins at the synpatic complex like Shank1, Shank2, GRIP1 ed IP3R1. When the team reduced expression of GluRδ2 in mice, the animals developed tremors similar to those seen in humans. Restoring GluRδ2 function suppressed the tremors, proving that the protein plays a key role in essential tremor. The team is also working to develop medications that increase GluRδ2 expression in the brain, which may reduce tremor.
The study opens several new possibilities for treatment of essential tremor. Sheng-Han Kuo, MD, study’s senior author and assistant professor of neurology at Columbia University Vagelos College of Physicians and Surgeons, said: “Past studies have identified changes in brain structure in people with essential tremor, but we didn’t know how those changes caused tremors. This study pins down how those structural changes affect brain activity to drive tremor. 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”.
The study is already published online in Science Translational Medicine.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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