Researchers from the Champalimaud Foundation shed light on the puzzling relationship between dopamine and rest tremor in Parkinson's disease, finding that preserved dopamine in certain brain regions may actually contribute to tremor symptoms, challenging common beliefs.
Parkinson's disease (PD) is a progressive neurological disorder known for its characteristic motor symptoms: tremor, rigidity, and slowness of movement. Among these, rest tremor-a shaking that occurs when muscles are relaxed-is one of the most recognisable yet least understood.
A new study from the Champalimaud Foundation published in npj Parkinson's Disease, led by the Neural Circuits Dysfunction Lab in collaboration with the Neuropsychiatry and Nuclear Medicine Labs, offers fresh insights into the complex relationship between rest tremor and dopamine, a chemical messenger that plays a key role in coordinating movement.
The Dopamine Paradox
Dopamine loss in brain regions like the putamen, associated with movement regulation, is a well-established hallmark of PD. However, while some patients experience significant tremor relief with dopamine replacement therapies like L-DOPA, others see little to no improvement, or even a worsening of symptoms. "Tremor is a common and often debilitating symptom for PD patients, but it has always been a bit of a puzzle", says Marcelo Mendonça, one of the study's lead authors. "We know dopamine is involved, but the way it affects tremor isn't as direct as with other motor symptoms".
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. "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", explains Mendonça. "This challenges our traditional understanding of how dopamine loss relates to PD symptoms".
An Overlooked Player in Tremor?
Using data from patients at the Champalimaud Clinical Centre and public databases, the researchers analysed information from over 500 patients. This diverse dataset included clinical assessments, DaT scans to visualise dopaminergic neurons, and wearable motion sensors that precisely measure tremor severity.
"Wearable motion sensors gave us a clearer, more objective measurement of tremor", says co-first author Pedro 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".
"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", continues Ferreira. "Our analysis suggests that the more dopamine activity preserved in the caudate, the stronger the tremor".
Senior author Joaquim Alves da Silva, head of the Neural Circuits Dysfunction Lab, picks up the story: "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", says 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.
Challenging Conventional Classifications
This study builds on earlier work by the same team, published last month in Neurobiology of Disease, 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 those 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.
This new study extends that line of inquiry, showing that the severity of rest tremor may be linked to specific brain circuits. "Dopamine loss in PD is not uniform-different patients may lose dopamine in distinct circuits", notes Alves da Silva. "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".
"Not all dopamine cells are alike", adds Mendonça. "They have different genetic makeups, connections, and functions. 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".
Implications for Treatment and Future Research
The team is already looking ahead, says Alves da Silva. "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".
The research highlights the importance of looking beyond general classifications in PD and underscores the need for more nuanced approaches informed by underlying biology. "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", concludes Mendonça.
