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The GABA hypothesis may explain what causes essential tremor.

What Causes Essential Tremor?

Essential tremor (ET) is the most common movement disorder. It is characterized by involuntary rhythmic shaking of the hands, arms, head, voice or other areas of the body. It may be more pronounced during a deliberate action, such as reaching for something, buttoning a shirt, combing hair, etc. It is not life-threatening, but most cases gradually become worse over time. Sometimes, the effects are debilitating and embarrassing.

Scientists and researchers have long been unable to identify the exact cause in the brain. A relatively new theory (the last two decades) called the GABA hypothesis has been put forth. I want to first explain what GABA is and how it does its job of regulating too much excitability in nerve cells.

GABA (gamma-aminobutyric acid) is a molecule produced in the brain. It functions as a chemical messenger, or neurotransmitter, to control certain brain activity. How it does this involves “binding” (joining) with receptors on the outer membrane (container) of a nerve cell (neuron) in the brain, rather like a key that exactly fits a lock. Just as the right key turns the lock and allows passage through a door, when GABA binds with its receptors, they respond by changing shape slightly, allowing ions (atoms or molecules with a charge) to pass in or out through the membrane. This changes the internal chemistry of the neuron in a way that makes it less excitable. For example, when a person is faced with a situation that creates fear or anxiety, neurons in certain brain areas become overexcited. If the fear became extreme, the person would be totally overwhelmed and become incapacitated to think or act. When a normal brain senses that fear is building, GABA “factory cells” release GABA into the brain so it is available to bind with its receptors on the overexcited. The channels open, the correct ions flow in, and the inside of the cell calms down which stops the chain reaction of growing fear. The person is then able to think things through and take appropriate action as needed. Thus, GABA is classified as an “inhibitory neurotransmitter”, meaning a nerve cell messenger that quiets things down.

So how does this relate to ET? The GABA hypothesis is currently considered the most robust explanation for what causes the tremors. Two areas of the brain, the cerebellum and the thalamus, are the areas that give rise to tremors. The cerebellum is rich in a type of cells that manufacture and release GABA, and they are particularly responsible for regulating and controlling motor movements. The GABA hypothesis suggests that four steps lead to ET:

  1. The GABA “factory cells” in the cerebellum begin to degenerate, and less GABA is produced.
  2. There is a drop in the GABA systems activity involving deep cerebellar neurons.
  3. The deep cerebellar neurons act as pacemakers, and without GABA to put the brakes on, they become like hyperactive children raising the energy level in the household.
  4. This affects the thalamus and the rhythmic tempo in its circuits speeds up, causing tremor.

As with any hypothesis, the only way to determine whether it’s the correct explanation is through laboratory studies and clinical research with animals and humans. For instance, imaging is becoming more advanced and therefore able to analyze deterioration of the cerebellar “GABA factory” cells – but the results are not always consistent. Likewise, autopsy analysis of brains does not always produce equal findings. So, while some evidence supports the GABA hypothesis, much needs to be done.

What does the GABA hypothesis mean for patients? If it is correct, then pharmaceutical agents aimed at stimulating GABA production/function, or synthetically supplementing it, would go into research and development. To date, many drugs such as gabapentin have been used in clinical studies, but success has by no means been universal.

For now, the only noninvasive, non-pharmaceutical intervention that offers the potential for durable reduction or elimination of tremor is MRI-guided Focused Ultrasound (MRgFUS). The Sperling Medical Group offers MRgFUS for ET using the Neuravive system. The outpatient procedure uses MRI guidance to identify the small area of the thalamus to be treated, allows treatment planning and mapping, and monitors the application of converging beams of ultrasound to generate sufficient destructive heat without damaging adjacent delicate tissues. The procedure is noninvasive and painless, and improvement in tremor is immediately evident. For more information, contact the Sperling Medical Group.

Gironell A. The GABA Hypothesis in Essential Tremor: Lights and Shadows. Louis ED, ed. Tremor and Other Hyperkinetic Movements. 2014;4:254. doi:10.7916/D8SF2T9C.

Essential Tremor