Dopamine-Resistant Tremors Caused by Abnormal Brain Activity, Study Finds

Dopamine-Resistant Tremors Caused by Abnormal Brain Activity, Study Finds

Parkinson’s patients whose tremors respond poorly to dopaminergic medications are likely experiencing abnormal brain activity outside the brain’s dopaminergic system, a study finds.

The results, “Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson’s tremor,” were published in the journal Brain.

The main cause of motor symptoms in Parkinson’s disease is a lack of dopamine — a key brain chemical — resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements. For that reason, levodopa, a dopamine replacement therapy, is often recommended to ease Parkinson’s symptoms.

“However, while dopaminergic medication effectively treats bradykinesia [slowness of movement] and rigidity, the effect on resting tremor is unpredictable and varies greatly between patients,” the researchers said.

“This observation casts doubt on the idea that Parkinson’s tremor has a dopaminergic basis,” they said.

One alternative explanation for the variability in treatment response is that tremors have different underlying causes depending on the patient. In some people, tremors indeed are caused by disturbances in the brain’s dopaminergic system — and for that reason, those patients respond well to dopaminergic medications. In other individuals, however, the tremors have a different underlying cause that these therapies are not able to tackle.

Researchers from the Donders Institute for Brain, Cognition and Behaviour, in the Netherlands, now set out to determine whether resting tremors that are resistant to dopaminergic medications are linked to abnormal brain activity in non-dopaminergic brain regions, such as the cerebellum, a region responsible for body balance.

To test this hypothesis, they first carried out a levodopa challenge, in which they administered the medication to 83 people with Parkinson’s who regularly experienced resting tremors. Their aim was to evaluate the patients’ response to the therapy.

After dosing, they selected the 20 participants who had the best treatment responses — tremors reduced by 71% after therapy — and the 14 patients who had the worst treatment responses. Those participants had their tremors reduced only by 6% after therapy.

Then, in the new subgroup of 34 patients with the best and worst responses to treatment, they used a technique called combined electromyography with functional magnetic resonance imaging (EMG-fMRI). That technique evaluated the participants’ tremor-related brain activity in two different settings: immediately after treatment with a placebo, or immediately after being treated with levodopa/benserazide combination therapy, administered at a dose of 50 or 200 mg.

Results showed that individuals whose tremors failed to respond to therapy had higher tremor-related brain activity in non-dopaminergic brain regions, including the cerebellum.

Conversely, in patients who had the best responses to treatment, analyses showed most tremor-related brain activity happened in dopaminergic brain regions. These regions included the thalamus, which regulates consciousness, sleep, and alertness, and the secondary somatosensory cortex, a region involved in pain processing.

In addition, researchers found that, in both groups, levodopa prevented abnormal brain activity associated with tremors in the thalamus. However, this protective effect was much stronger in people who responded well to dopaminergic medications compared with those who responded poorly to treatment.

“These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine,” the investigators said.

“These findings may have therapeutic implications, suggesting that an alteration of cerebellar reactivity and/or tremor-related processing may improve the clinical dopamine response of tremor,” they added.

Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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6 comments

  1. Marc Alexander says:

    My tremor is not significantly reduced by levodopa, but DBS effectively eliminated it. I am confused by your article. Is there some way to alter cerebellar reactivity? What agent is used?

    • sam spurling says:

      Mine is the same way tried levodopa for a month 2 tablets 3 times a day nothing. I have no other issues except tremor on left side. Doctors say that I first must respond to treatment before DBS can be considered.

  2. Carol Defoe says:

    My right leg tremor can only be stopped by taking one half of a 10mg. Tramadol tablet. My doctor’s don’t know why it works but it does. I usually only need to do this twice a day, therefore, one tablet, (2 halves) a day is a very minimal dose.

    • Margie says:

      My husband’s symptoms best fall under Cordial Basil disease. His movement specialist said it is very rare and much is unknown on how to treat it. PD medications are not much help. Right side tremors and leg cramps continue even at rest. He also has dementia which rules out DBS. Is there much research in this field?

  3. W.Dyer says:

    MRgFUS (focused ultrasound) is recently in trials to stop/reduce tremor in both PD and ET. The technology is used to perform both pallidotomy and pallidothalamic tractotomy. Which of these two would the recent research favor?

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