$9M Boost for Safer Parkinson's Treatment Methods

Team Mackenzie will join ASAP's Collaborative Research Network (CRN), an international, multidisciplinary, multi-institutional network working to address high-priority research questions about Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder most commonly associated with motor symptoms such as stiffness, balance difficulties, and slow movements. However, many patients also suffer from psychiatric and cognitive symptoms such as depression, anxiety, apathy, and lack of motivation - sometimes long before the motor problems become apparent. Although these symptoms are common, they are significantly less well understood and more difficult to treat.

"The psychiatric and cognitive symptoms of Parkinson's disease are common and severely distressing for patients. However, these symptoms are still poorly understood. Depression, for example, is the most common psychiatric symptom in Parkinson's disease and affects women and men to roughly the same extent. We want to understand where in the brain these symptoms arise and whether they share mechanisms with the motor symptoms - or whether they involve distinct neural circuits," says Åsa Mackenzie, research team leader at Lund University, Sweden, and lead investigator of the research project.

This is not something a single research group can do on its own. Collaboration between labs with complementary skillsets is absolutely crucial, and there is a strong shared drive within the team to tackle these difficult questions.

Early symptoms may offer new opportunities

A particular challenge is that psychiatric and cognitive symptoms can often appear early in the course of the disease - so-called prodromal symptoms - before Parkinson's disease has been diagnosed.

"Many people who will later be diagnosed with Parkinson's disease seek care for conditions such as depression or anxiety several years before motor symptoms appear. At present, there are no reliable ways to link these psychiatric and cognitive symptoms to Parkinson's disease, which makes diagnosis difficult. If we can better understand the underlying biology, this could eventually open up new opportunities for earlier diagnosis, and both symptomatic and disease-modifying treatments targeting this kind of non-motor symptoms," Mackenzie states.

Focus on a brain area of great clinical significance

The project takes its starting point in a small but highly significant area of the brain used in deep brain stimulation (DBS) treatment. DBS is an established treatment for Parkinson's disease and involves surgically implanting electrodes into the brain to modulate abnormal neural circuit activity.

"We know that stimulation in and around the subthalamic nucleus can alleviate a range of symptoms depending on the exact location of the stimulation. This approach is best known for treating severe motor symptoms in Parkinson's disease. Importantly, the same brain area, albeit a slightly different position, is also a DBS target for treatment of obsessive-compulsive disorder (OCD), and new studies suggest that neighbouring regions have therapeutic effects on treatment-resistant depression. So, it is already known that small adjustments in electrode placement can have major consequences, including both therapeutic benefits and adverse side effects," Mackenzie elaborates.

Clinical and experimental mapping

The project consists of two closely integrated parts - experimental and clinical - aiming to better understand the underlying anatomy and function of the DBS target area. In the clinical part, brain regions in patients are mapped and correlated with where electrodes are placed during DBS and which symptoms are affected. The goal is to provide better guidance on where stimulation should - and should not - be applied.

The main part is focused on experimental neuroscience and aims to deliver detailed mapping of neural circuit function and dysfunction in animal models.

"We have identified molecular markers that, for the first time, allow us to distinguish between neighbouring regions previously regarded as a single structure. This makes it possible to analyse which nerve cells regulate specific behaviours, such as those linked to depression or anxiety, and what their connections look like in the brain."

Significance for several brain disorders

The knowledge gained from the project could have broad implications beyond Parkinson's disease. Similar target areas for DBS are used, for example, in obsessive-compulsive disorder, Tourette's syndrome and dystonia, and are also being tested for treatment-resistant depression.

"The effect of DBS varies greatly across several of these conditions. A more detailed molecular and anatomical map could help us understand why the treatment works for some but not for others and ultimately inform more precise and personalized treatment approaches."

"In addition to improving knowledge of psychiatric and cognitive symptoms in Parkinson's disease and helping towards improved precision in DBS, the data will inform pharmaceutical drug discovery."

Major international collaboration

"This is not something a single research group can do on its own. Collaboration between labs with complementary skillsets is absolutely crucial, and there is a strong shared drive within the team to tackle these difficult questions," concludes Åsa Mackenzie.