Parkinson’s Symptom, Resting Tremor, Relates to Dopamine in Unexpected Way

Parkinson’s disease (PD) is a progressive neurological disorder known for its characteristic motor symptoms, which include tremor, rigidity, and slowness of movement. Among these, rest or resting tremor (RT)—a shaking that occurs when muscles are relaxed—is one of the most recognizable yet least understood.

A new study from the Champalimaud Foundation offers fresh insights into the complex relationship between resting tremor and dopamine (DA), a chemical messenger that plays a key role in coordinating movement. Led by scientists at the Neural Circuits Dysfunction Lab, in collaboration with the Neuropsychiatry and Nuclear Medicine Labs, the researchers’ analysis of data from around 500 patients indicated that preserved dopamine in certain brain regions may actually contribute to tremor symptoms, challenging common beliefs.

“Paradoxically, we discovered that patients who exhibit tremor have more dopamine preserved in the caudate nucleus, a part of the brain important for movement planning and cognition,” explained Marcelo Mendonça, PhD, one of the study’s lead authors. “This challenges our traditional understanding of how dopamine loss relates to PD symptoms.”

The findings highlight the importance of looking beyond general classifications in PD and underscore the need for more nuanced approaches informed by underlying biology, which could ultimately help to inform on therapeutic strategies. “By identifying the specific neural circuits involved, we hope to clear the mist surrounding the heterogeneity of PD symptoms and contribute to more precise interventions that can improve the quality of life for those affected by this disease,” Mendonça concluded.

Mendonça is co-senior author of the team’s published paper in npj Parkinson’s Disease, titled “Integrity of dopaminergic terminals in the caudate nucleus is relevant for rest tremor in Parkinson’s disease,” in which they noted, “A better understanding of the tremor circuit and the refinement of the current model of PD RT can provide important insights into PD pathophysiology.”

Dopamine loss in brain regions including the putamen, associated with movement regulation, is a well-established hallmark of PD. “Dopamine (DA) loss is necessary for rest tremor (RT) to be present …” the authors stated. However, while some patients experience significant tremor relief with dopamine replacement therapies, such as L-DOPA, others see little to no improvement, or even a worsening of symptoms. “This suggests that the link between dopamine depletion and RT is more complex than a simple DA dose dependency model, the team further noted, “Resting tremor (RT) is a Parkinson’s disease (PD) symptom with an unclear relationship to the dopaminergic system.” 

Added Mendonça, “Tremor is a common and often debilitating symptom for PD patients, but it has always been a bit of a puzzle. We know dopamine is involved, but the way it affects tremor isn’t as direct as with other motor symptoms.”

Using data from patients at the Champalimaud Clinical Centre and from public databases, the researchers analyzed information from around 500 individuals. The diverse dataset included clinical assessments, DaT scans to visualize dopaminergic neurons, and wearable motion sensors that precisely measure tremor severity.

Conventional wisdom suggests that less dopamine should correspond to more severe symptoms. However, the researchers found the opposite to be true when it comes to rest tremor. “By combining imaging data with measurements from these sensors, we observed a clear link between dopamine function in the caudate nucleus and global severity of resting tremor,” said co-first author Pedro C. Ferreira. “Our analysis suggests that the more dopamine activity preserved in the caudate, the stronger the tremor … Wearable motion sensors gave us a clearer, more objective measurement of tremor.”

Senior author Joaquim Alves da Silva, head of the Neural Circuits Dysfunction Lab, commented, “This is the first large study to clearly show a link between better-preserved dopamine levels in the caudate and the presence of rest tremor. Although patients with rest tremor have lost dopamine-releasing nerve endings in the caudate, they actually have more of these nerve endings preserved compared to patients without tremor.”

One of the most intriguing findings of the study was that the more dopamine was preserved in the caudate on one side of the brain (each hemisphere has its own caudate), the more tremor there was on the same side of the body. “This was quite unexpected,” said Alves da Silva. “Usually, each side of the brain controls movement on the opposite side of the body.” Their computational model found that this “same-side” effect could arise spuriously from two factors: the generally higher dopamine in both caudates in tremor patients and the uneven way PD affects each side of the brain.

This study builds on earlier work by the same team, published last month, which showed the value of treating rest tremor separately from other motor symptoms—a departure from traditional approaches that have lumped these symptoms together.

Their prior research revealed that rest tremor varies with the type of PD progression. Tremor, particularly when resistant to treatment, is more common in patients presenting a “brain-first” PD, while patients without tremor present a symptom pattern more aligned with a “gut-first” PD, where the disease process starts in the gut and spreads to the brain. “Tremor has been linked with PD forms with a better prognosis,” the scientists wrote in their newly published report.

This new study extends the previous line of inquiry, showing that the severity of rest tremor may be linked to specific brain circuits.

“We build on current RT models and demonstrate that the integrity of caudate dopaminergic terminals is linked to the presence and development of RT,” the authors stated. “This relationship is supported by pre-clinical evidence that alterations in caudate cholinergic or dopaminergic systems can lead to the development of tremor.” Added Ferreira, “On the surface, patients with and without dopamine loss in the caudate seem similar. However, sensors reveal subtle differences in tremor oscillations that traditional clinical rating scales might miss, and they’re relatively easy to use, allowing us to reliably connect symptoms with what’s happening in the brain.”

Alves da Silva further commented, “Dopamine loss in PD is not uniform—different patients may lose dopamine in distinct circuits. By focusing on rest tremor in isolation, we are in a better position to pinpoint the specific neural pathways involved. For instance, could tremor result from an imbalance in dopamine between the caudate and putamen? Identifying reliable biological correlates for individual symptoms is critical, as it paves the way for more targeted therapies aimed at relieving them.”

Mendonça in addition pointed out that “Not all dopamine cells are alike.” They have different genetic makeups, connections, and functions, the author stated. “This means that which cells a patient loses or keeps could affect their symptoms. For example, tremor might be tied to the loss or preservation of specific dopamine populations that connect to certain brain areas. This variation in cell type loss could further explain the wide range of symptoms among PD patients.”

The investigators further pointed out, “Individual genetic heterogeneity interacting with the vulnerability associated with the specific genetic signature of a neuron may lead to different subpopulation losses and therefore different phenotypes. Within this model, tremor may emerge as a byproduct of specific circuits integrity and general neuronal resilience to death.”

The team is already looking ahead, Alves da Silva stated. “It’s difficult to establish causality between dopamine preservation in the caudate and rest tremor in humans, which is why we’d like to test this in animal models, where we can manipulate specific cells and observe the effects on tremor. We’d also like to use advanced imaging techniques, like high-resolution dopamine PET scans and MRI, to identify key nodes in the dopamine system and link them to specific motor symptoms. This approach could help us better understand why PD symptoms differ from one patient to another.”