Shedding Light on Parkinson's
Dr Louise Parr-Brownlie works as a neuroscientist and lecturer in the University’s Brain Health Research Centre and is one of an exclusive group of researchers dotted around the world in the midst of a revolution in brain science. In her Parkinson’s disease research, Louise is using a cutting-edge technology called optogenetics, which allows scientists to ‘switch’ individual brain cells on and off with the use of a laser light, allowing precise control of the cell’s behaviour – particularly relevant in Louise’s research where movement function is involved.
Ultimately, it is hoped that one day the activation of deactivation of neurons with the use of light pulses could restore movement or settle down involuntary movement in patients with Parkinson’s disease.
Louise was awarded funding by the Neurological Foundation in 2009 to gather critical information about the dysfunctional brain activity that causes the movement deficits of Parkinson’s disease. The project has employed optogenetics to control brain activity in an animal model of Parkinson’s disease and is the first study of its kind in New Zealand. The optogenetics technique is both groundbreaking and complex but for neuroscientists it is proving an exciting new direction for research because it provides a precise way of controlling neural activity in the brain.
In 2010 a collaboration of scientists at the Stanford University School of Medicine and University of California-San Francisco showed that by stimulating a specific circuit of neurons they could restore normal movement in mice with Parkinson’s disease.
Because optogenetics has this ability to target specific neurons, the prospect for use in future treatment therapies is promising.
There is no cure for Parkinson’s disease, and current drug therapies can be slow-acting. The most commonly prescribed drug, L-dopa, causes dyskinesias (involuntary movements) in most patients within 10 years of starting this treatment. Electrical stimulation treatment such as DBS (Deep Brain Stimulation) is useful, but targets a general cell area of the brain rather than individual cells. In New Zealand most people with Parkinson’s are treated with drug therapies, though some patients have been selected for DBS (which has only been available at Auckland City Hospital since 2009), but the safety criteria and cost limits accessibility for many patients.
Louise and her team’s research over the last couple of years has mainly focused on a part of the brain called the motor thalamus – an important link in what scientists call the ‘motor pathway’, or the route of nerve cell activity that allows us to initiate movement. Few studies globally have examined how motor thalamus activity changes in Parkinson’s disease and this has left a gap in the understanding of what role, if any, the thalamus plays in movement deficits in Parkinson’s patients.
The motor thalamus is a critical intersection for the passage of motor information from the basal ganglia to the motor cortex and Louise’s initial experiments have been conducted in either anaesthetised rats or those in resting states. Louise places recording electrodes in the brain to record ‘electrical events’ that occur with brain activity. To her team’s surprise, activity in this area did not appear to be altered in the Parkinsonian brain and Louise’s team is now exploring the possibility that activity is selectively altered when movements are dysfunctional, i.e. bradykinetic (or slowed).
Alongside this research, Louise has been exploring the affect that basal ganglia activity has on motor thalamus activity with the use of the revolutionary optogenetic technique. The basal ganglia are important for selecting the appropriate motor signals to transmit to your muscles and Louise says scientists already know that Parkinson’s disease somehow alters basal ganglia activity.
“What I want to find out is what is happening in this motor circuitry that might explain precisely why patients have movement deficits. By learning how the motor thalamus works and is affected by Parkinson’s disease, we may discover now treatment sites. I won’t develop a new drug, but I may find new ways to optimise the use of existing drugs. It is also possible, through optogenetics, that we will find a new site for deep brain stimulation,” she says.
Optogenetics involves combining gene therapy to make brain cells light-sensitive and light to stimulate them. Brain cells are stimulated using optogenetic technology, cell activity is simultaneously recorded in the next stage in the motor pathway and any downstream effects that are seen in behaviour and movement are also noted. If this research can establish which parts of the brain circuits are affected in Parkinson’s disease the cells involved could be specifically targeted with drug therapies or more accurately directed DBS.
Louise says her research and the optogenetics studies of international laboratories provide hope for potential treatments for other neurodegenerative diseases. “Many neurodegenerative diseases and neurological disorders involve changes in the basal ganglia function, including Huntington’s disease, ADHD and Restless Legs Syndrome. New information about changes in the motor pathways in the brain in Parkinson’s disease will always improve our understanding of all disorders involving the basal ganglia.”
So how does a scientist at the bottom of the world become involved in the futuristic frontiers of brain science? Louise says that with today’s communication technology it is easy to stay in touch with mentors and collaborators around the world. “Their support and discussion always challenge my ideas and make me think outside the square,” she says. Louise worked as a postdoctoral fellow at the National Institute for Neurological Disorders and Stroke at the National Institutes of Health (NIH) in Washington DC for four and a half years from 2003, and still collaborates with her supervisor, Dr Judith Walters, who is now chief of the Neurophysiological Pharmacology Section at NIH.
Louise also notes that the University of Otago’s Brain Health Research Centre operates at the level of other world-leading neuroscience institutions and maintains many clusters of neuroscience research excellence. “It was great to experience the vitality and opportunities that a big city like Washington has. However, I am very happy to be home. I love the research environment at Otago. It is collaborative, supportive, has strategic vision for the resources we will need in the future and has a focus to translate basic research to the clinic.”
Louise’s greatest challenges as a scientist are the same as those of her international colleagues. “Having enough time and getting enough money! We always have new experiments that we could do to test new ideas and potential treatments. To carry out experiments we need to employ research staff to do most of the bench work and we need to buy the equipment and consumables that we need to do the experiments. Another challenge is to prioritise the next question that we must address and then to design the perfect experiments to answer that question. The grant from the Neurological Foundation has enabled me to do the experiments that I have dreamed about for several years and was pivotal in my appointment as a lecturer in the Department of Anatomy, an important career step for a young scientist.”
The next few years of research will be exciting for Louise, and motivation is always nearby. “My discussion with Parkinson’s patients, and their families, always reinforces the urgent need for improved treatments and quality of life. It is a privilege to be able to do a job I love and help improve our understanding of this serious disease.”
In recent years, Louise has also witnessed the heart-breaking effects of a brain disorder first-hand. “My husband was diagnosed with complex regional pain syndrome two years ago, so I am reminded daily of the devastating effects a neurological disorder can have on someone’s life and the challenges they have to overcome.”