Scientists delve into how repairing dysfunctional brain circuits in Parkinson’s can offer another path forward for new treatment strategies.
Parkinson’s is a debilitating disease marked by loss of brain cells that produce a chemical called dopamine, which regulates voluntary movement. In the United States, it is the second most common neurodegenerative disorder after Alzheimer’s disease, with an approximate 500,000 affected individuals, though experts speculate the true number is closer to one million people.
Hong-yuan Chu works as an assistant professor at the Van Andel Institute in the US and has dedicated his career to aiding patients afflicted with Parkinson’s disease. On his website he writes that his lab’s long-term goal is to develop strategies that target brain cells to not just treat symptoms, but to stop them developing in the first place.
To do this, his group has taken a different approach to understanding how the brain changes during Parkinson’s and what this could mean for new, lasting therapies.
Diving into the thalamus and cortex
Within the field it is widely accepted that motor dysfunction in patients with Parkinson’s is caused by a loss of dopamine cells, which leads to “abnormal interactions” between a group of linked brain structures called the basal ganglia and the thalamus and cortex.
The thalamus is a small structure within the brain located just above the brain stem between the cerebral cortex and the midbrain. It has extensive nerve connections to both, with its primary function being to relay motor and sensory signals from different parts of the body to the cerebral cortex.
According to Chu, this interaction is critical for sensory perception, motor control, and cognition, with dysfunction likely to contribute to various symptoms experienced by people with Parkinson’s. However, its exact role has been under explored, leaving a gap that Chu and his team hoped to fill.
“While most research on brain dysfunction in Parkinson’s focuses on the basal ganglia, our study took a different approach by examining circuits between the thalamus and the cortex,” explained Chu in an email.
“We aimed to determine whether the observed changes between the thalamus and the cortex were caused by the [diseased] information flow from the basal ganglia,” he continued. “Surprisingly, we found a significant reduction in connectivity between the thalamus and the cortex in a [Parkinson’s] state, […] and the reduction only occurred within a specific subtype of cortical neurons.”
Repairing broken circuits
While there is currently no cure for Parkinson’s disease, significant progress has been made over the last few decades to help manage symptoms and improve quality of life. “[The drug] levodopa and deep brain stimulation are two broadly used therapies to manage motor symptoms of Parkinson’s,” said Chu.
But he believes we can do better. “In the brains of people with Parkinson’s, there are ongoing abnormal brain rhythms […], which are believed to be the signals that prevent people with Parkinson’s from moving,” he explained. “Given that the thalamocortical network is also part of this rhythmic system, we wondered whether the broken circuits between the thalamus and the cortex in Parkinson’s may be rescued by suppressing the pathological rhythm.”
To test this hypothesis, the team used designer receptors exclusively activated by designer drugs (or DREADDs for short), which are a class of engineered protein receptors that are activated by specific molecules. In animal models, they allow scientists to control nerve cell activity and manipulate desired neurons.
Using high-resolution images of the regions cellular and synaptic structures, they were able to quantify the connections between the thalamus and the cortex in mouse models of Parkinson’s, finding that certain broken circuits in the thalamus and cortex can be repaired by suppressing the disease-related messages from the basal ganglia.
“We used them to stop the flow of pathological information between the basal ganglia and the thalamus,” said Chu. “Neural circuit manipulation using this approach partially restored the connectivity between the thalamus and the cortex, supporting our original idea about what might happen.
“This new information moves our understanding of Parkinson’s pathophysiology to the next level,” he continued. “In other words, we cannot treat the cerebral cortex as a single homogenous entity and will need multi-scale research to study cortical abnormalities in Parkinson’s, particularly in fine scales.”
Implications for current therapies
In the brains of patients with Parkinson’s disease, the thalamus and the cortex participate in a broad network of abnormal signals and patterns. “Nerve cells in these brain regions fire together in a highly synchronized abnormal pattern,” explained Chu.
He speculates that both widely used dopamine-based medications and deep brain stimulation could be helping to reduce the level of abnormal activity in the cerebral cortex. However, he says, it is yet to be determined whether and how such cortical network changes may contribute to symptomatic alleviation by either dopamine-based medications or deep brain stimulation.
“Answers to these questions may help us to design individualized strategies for future Parkinson’s treatment,” he said
The team stress that while these initial findings are significant, more research is needed to confirm. “This work is very exciting, but like many other scientific studies, it raises more questions than it answers,” said Chu. “It provides a foundation for future exploration of the role of other elements of the connections between the thalamus and the cortex in Parkinson’s pathophysiology.
“In the long term, we plan to build on our in-depth understanding of brain network dysfunction. We hope to one day translate our findings into better treatments for people with Parkinson’s,” he added.
Reference: Hong-Yuan Chu, et al., Reduced thalamic excitation to motor cortical pyramidal tract neurons in parkinsonism, Science Advances (2023). DOI: 10.1126/sciadv.adg3038
Feature image credit: Courtesy of Van Andel Institute