Researchers at the Champalimaud Foundation have shed light on the enigmatic relationship between dopamine and resting tremor in Parkinson’s disease, discovering that dopamine preserved in certain brain regions may actually contribute to tremor symptoms, calling into question common beliefs.

Parkinson’s disease (PD) is a progressive neurological disorder known for its characteristic motor symptoms: tremor, rigidity, and slowness of movements. Among these, rest tremor; a jerk that occurs when muscles are relaxed – ; is one of the most recognizable but least understood.

A new study from the Champalimaud Foundation published in npj Parkinson’s diseaseled by the Neural Circuits Dysfunction Lab in collaboration with the Neuropsychiatry and Nuclear Medicine Laboratories, offers new insights into the complex relationship between resting tremor and dopamine, a chemical messenger that plays a key role in movement coordination.

The dopamine paradox

Loss of dopamine in brain regions such as the putamen, associated with movement regulation, is a well-established feature of PD. However, while some patients experience significant relief from tremor with dopamine replacement therapies like L-DOPA, others experience little or no improvement or even worsening of symptoms.

Tremors are a common and often debilitating symptom in Parkinson’s patients, but they have always been a headache. We know dopamine is involved, but the way it affects tremor is not as direct as it is for other motor symptoms.”

Marcelo Mendonça, one of the main authors of the study

Conventional wisdom suggests that less dopamine should correspond to more severe symptoms. However, researchers found the opposite when it came to resting tremors. “Paradoxically, we found that patients who present with tremor have more dopamine stored 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 is linked to Parkinson’s symptoms.”

An overlooked player in tremor?

Using patient data from the Champalimaud clinical center and public databases, researchers analyzed information from more than 500 patients. This diverse dataset included clinical assessments, DaT scans to visualize dopamine neurons, and wearable motion sensors that accurately measure tremor severity.

“Wearable motion sensors have given us a clearer and more objective measurement of tremors,” says co-first author Pedro Ferreira. “On the surface, patients with and without loss of dopamine in the caudate appear similar. However, the sensors reveal subtle differences in tremor oscillations that traditional clinical rating scales might miss, and they are 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 dopaminergic function in the caudate nucleus and overall resting tremor severity,” continues Ferreira. “Our analysis suggests that the more dopaminergic activity is preserved in the caudate, the stronger the tremor.”

Lead author Joaquim Alves da Silva, head of the Neural Circuit Dysfunction Lab, takes 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 resting tremors. with resting tremor, have lost the 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 tremors there were on the same side of the body. “It was quite unexpected,” says Alves da Silva. “Usually, each side of the brain controls the movements of the opposite side of the body.” Their computer model revealed that this “same-side” effect could spuriously arise from two factors: the typically higher dopamine in both caudates in tremor patients and the uneven way in which PD affects each side of the brain.

Difficult conventional classifications

This study builds on previous work by the same team, published last month in Neurobiology of diseaseswho showed the benefit of treating resting tremors separately from other motor symptoms; a departure from traditional approaches that have grouped these symptoms together. Their previous research found that resting tremor varies depending on the type of PD progression: tremor, especially when resistant to treatment, is more common in patients with “brain-first” PD, while those without tremors have a pattern of symptoms more aligned with a “brain first” “gut first” Parkinson’s disease, where the disease process begins in the gut and spreads to the brain.

This new study extends this line of research, showing that the severity of resting tremors 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 resting tremors in isolation, we are in a better position to identify the specific neural pathways involved. For example, could tremors result from an imbalance of dopamine between the caudate and putamen? “Identifying reliable biological correlates for individual symptoms is essential, as it paves the way for more targeted therapies aimed at alleviating them.”

“Not all dopamine cells are the same,” adds Mendonça. “They have different genetic makeups, connections and functions. This means that the cells a patient loses or retains can affect their symptoms. For example, tremors may be linked to the loss or preservation of dopamine populations “This variation in cell type loss could further explain the wide range of symptoms among Parkinson’s patients.”

Implications for treatment and future research

The team is already looking to the future, says Alves da Silva. “It is difficult to establish a causal link between preservation of dopamine in the caudate and resting tremor in humans, which is why we would like to test this in animal models, where we can manipulate specific cells and observe the effects on tremor We would also like to use advanced imaging techniques, such as high-resolution dopamine PET and MRI, to identify key nodes of 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 of Parkinson’s disease and highlights the need for more nuanced approaches informed by the underlying biology. “By identifying the specific neural circuits involved, we hope to clear the fog surrounding the heterogeneity of Parkinson’s disease symptoms and contribute to more precise interventions that can improve the quality of life of those affected by this disease,” concludes Mendonça .