Professor Vasileios Christopoulos, Assistant Professor of Bioengineering at the University of California, Riverside, gained a five-million-dollar grant from the National Institutes of Health (NIH) to study action regulation in Parkison’s patients that will undergo Deep Brain Stimulation (DBS) to ultimately improve DBS treatment and model action regulation mechanisms happening in the brain. The study started in the summer and will proceed over a five-year period, which will take place at Cedars Medical Center in Los Angeles and UT Southwestern Medical Center in Dallas. Two hundred patients will receive surgically implanted electrodes within the brain in accordance with DBS procedure.
According to Professor Christopoulos, Deep Brain Stimulation is a United States Food and Drug Administration approved treatment for intense cases of Parkinson’s, epilepsy, depression, and other neurodegenerative and psychiatric diseases. The procedure includes a hole drilled into the brain and long electrodes implanted at certain areas, which will be stimulated with electrical current. During the surgery, patients are usually awake and are asked to perform tasks to determine the effectiveness of the electrode placement. Often, the surgeon decides the commands they want the patient to demonstrate or will notice if symptoms, such as tremors, are alleviated. Which does not necessarily target the areas Professor Christopoulos will explore.
In this study, Professor Christopoulos explains, the electrodes will be implanted in the subthalamic nucleus and other areas of the old brain. Electrodes will also be attached to the new brain, the cortex, to collect data on how both brain areas interact to modulate stop-and-go commands. While the new brain is responsible for higher-level thinking and planning, the old brain is tasked with more survival functions, such as moving and breathing. Therefore, both parts are essential for understanding the network of action regulation. The patient’s behavior will be monitored by how they play a joystick-controlled video game that was developed by Professor Christopoulos’ lab.
Professor Christopoulos explains that the patient will have a joystick attached to the bed, and a screen placed in front of them will display one target on the left, on the right or both targets. When one target is shown, they will move the joystick’s cursor to the target, which represents instructed movement. If there are two targets displayed, then a decision problem is represented, and the decision circuit can be activated. The game also includes a stop task for when the targets turn red, thus activating the “stopping network.” Professor Christopoulos focuses on only activating the activation regulation network to understand the “computations underlying action regulation” and what is causing malfunctioning in the brain.
According to Professor Christopoulos, the lab sent the video game to the patients; data was collected from UCR students playing the game. Thus giving the lab the opportunity to see the differences in performance of young, healthy subjects and Parkinson’s patients.
The data collected from the patients and students will be used to, as Professor Christopoulos says, “develop mathematical models and computation numbers that explain how the brain regulates action.” The model will hopefully explain how people decide to stop or continue their actions and change plans in the midst of doing an action. In understanding how the mechanisms behind action regulation function in a normal, healthy brain, both scientists and doctors will be able to understand the driving forces in an abnormal functioning brain. Thus being able to improve existing treatments and, possibly, create new technology or medicine. Professor Christopoulos states that “you cannot fix something if you cannot understand the problem,” which is one of the many reasons that drive his research.
During the interview, Professor Christopoulos described neuromodulation treatments as “a more modern way to treat neurological and psychiatric disorders.” Neuromodulation relies on stimulating the brain with electricity, not by drug procedure. Stimulation can be done invasively or non-invasively, but the goal is the same — “to modulate brain networks” to resolve the underlying neurological problem.
DBS, or other forms of neuromodulation, tries to remedy a problem without fully understanding the circuits of the brain; therefore, treatments could cause other problems in certain cases. Professor Christopoulos points out that DBS may stop tremors; however, it could also “create other neurological deficits,” which is his main reason for creating the computational model of motor regulation. He wants to understand the regulations in order to “develop treatment” that will be the best fit for particular diseases.
He states that the “main issue” with the technology is that treatments are not patient-specific when “not one will work for everyone.” He explains that just as drug dosage depends on the patient, so does the voltage, pulse and strength of the stimulation of neuromodulation. Without studying the brain networks, medical professionals cannot tailor the technology for each patient, which could be the difference between alleviating the disease and causing other deficits.
As excited as Professor Christopoulos is for the upcoming study, he opens up about the difficulties he faced in creating the experiment. When working with human subjects, Parkinson’s patients, the experiment cannot proceed longer than the clinical protocol that is already approved for DBS. The study was adapted to the clinical procedure to accommodate the proper standard of care, regardless of the experiment. Therefore, he is using patients who will undergo DBS whether the experiment is conducted or not, which was one of the reasons that led to approval for testing.
He expresses that “the most challenging part” of creating a behavioral task is developing a procedure that can be run and replicated in the lab and is representative of real life. He states that the task “cannot be very complicated” because he wants to pinpoint specific areas of the brain involved so that the lab can monitor the behavior. However, it also cannot be very simple in the case that the brain will operate differently. He expresses that the experimental design is what takes longer than performing the actual experiment.
Another problem that he ran into was the minimization of confounding variables. When performing the experiment, it is important to make sure all the subjects are treated and tested in the same way so that they are valid and comparable. For example, when he did the experiment with UCR students, where the students sat, where they performed the task, how the students were treated, and the overall procedure of how the experiment was conducted must be uniform because “behavior” is “very sensitive.” In behavior, it is common that small changes in procedure can lead to large changes in the subject’s behavior, which will influence the results of the study.
Overall, the most important concept to understand, according to Professor Christopoulos, is to make sure not to oversimplify the model to the point where it affects the nature of the problem. Even when adjusting the procedure to compensate for confounding variables, Professor Christopoulos keeps in mind the influence changes may have on the validity of the study.
When the model is achieved, Professor Christopoulos’ next step will be to test different stimulation protocols within the model to uncover the best conditions for each different procedure. Instead of taking more patients to test and collecting data over many years, he can run the protocols in the computational model to determine the more effective conditions for the treatment.
The model can also be applied to patients with similar diseases such as Tourette syndrome, Obsessive Compulsive Disorder, or essential tremor. He states that the diseases are all “under the same umbrella” that affects action regulation, which can be expanded into the model in coming experiments. As for now, the Christopoulos Lab will await the data that can be analyzed to develop the action regulation model.
If interested in learning more about the Christopoulos lab and their work, please see their website.
