Clinical Trials of Movement Disorders: An Interview With Dr. Robert Chen
By: Samia Tasmim
Dr. Robert Chen is the Catherine Manson Chair in Movement Disorders, a Professor of Medicine (Neurology) at the University of Toronto, the Director of the Eliot Phillipson Clinician-Scientist Training Program, and a Senior Scientist at the Krembil Research Institute. After completing high school in Hong Kong, Dr. Chen obtained his MB BChir at the University of Cambridge in England, where he first developed an interest in neurology during medical school training. In particular, he found it fascinating that different neurological diseases had different manifestations, and that by using the knowledge of anatomy and physiology, it was possible to deduce the location and nature of patients’ problems. This led him to complete a Master’s degree at the University of Toronto, under the tutelage of Dr. Peter Ashby, which was followed by residency in internal medicine at Queen’s University and further residency training in neurology at Western University. At this time, Dr. Chen studied the mechanisms of breathing and developed an interest in movement disorders, including Parkinson’s disease (PD). Techniques like magnetic brain stimulation, electroencephalography (EEG), and functional imaging further piqued his interest during a fellowship at the National Institutes of Health (NIH) in the United States. This became the focus of his research when he returned to Toronto.
Currently, Dr. Chen has research interests in four main areas:
- Transcranial magnetic stimulation (TMS): Dr. Chen and his team study cortical inhibition and facilitation, and the connection between brain areas. His team has conducted clinical trials using TMS, and has established methods to study connections between cortical circuits, including double and triple pulse paradigms. These paradigms have been used to understand the pathophysiology of PD and dystonia, disorders in which cerebellar and cortical connections are abnormal.
- Deep brain stimulation (DBS):DBS is a treatment used in dystonia and PD, as well as in depression. Dr. Chen and his team have used DBS electrodes to record from deep brain areas, such as the basal ganglia, which send signals for initiating and stopping movement. Dr. Chen’s team was able to record electrical signals from the subthalamic nuclei, and then stimulate these areas at those specific frequencies. As there is a person-to-person variability in the peak frequencies, by stimulating at patient-specific frequencies, they study how changes in stimulation affect patients with PD.
- EEG and Magnetoencephalography (MEG) studies: Dr. Chen and his team utilize DBS evoked potentials for source localization through EEG and MEG. For example, stimulation of the basal ganglia enables the identification of localized cortex activation as well corresponding timing. They are also using EEG in dystonia and PD as a potential biomarker and predictor of treatment like DBS, focusing on an analysis technique called phase amplitude coupling (PAC).
- Functional Magnetic Resonance Imaging (fMRI): Dr. Chen’s team examines the effects of sensory stimuli on activation of the sensory cortex, particularly in dystonia patients with “writer’s cramp” who develop voluntary contractions when they write. Dr. Chen and his group found that this condition is associated with abnormal digit representation in the sensory cortex, and, in some cases, there is an inversion of somatotopy. In contrast, people without the condition have a very orderly digit representation. Another finding from PD patients was that certain areas of sensory cortex have increased or decreased activation compared to controls, which may account for some of the observed differences between groups. They have also looked at the effect of repetitive TMS on functional connectivity. In this project, they used theta burst stimulation of the cerebellum to see how it changes resting-state connectivity from the cerebellum to different cortical networks.
Dr. Chen and his team have conducted previous clinical trials and continue to be actively engaged in new ones. One such trial assessed the effects of repetitive magnetic brain stimulation in PD to treat motor symptoms and depression. This was a multicenter collaborative effort between the Toronto Western Hospital (TWH), the Brigham and Women’s Hospital (Boston), University of Florida, Cleveland Clinic, the New York University, and University of North Dakota. The stimulation was aimed at both the motor cortex and dorsolateral prefrontal cortex (DLPFC). It was a randomized control trial (RCT) with a “realistic” sham procedure, as sham stimulation was delivered with similar sound and sensation to those receiving real stimulation. The main findings demonstrated that the motor signs and symptoms of PD improve compared to sham, but interestingly, there were no effects on depressive symptoms.
Currently, Dr. Chen and his lab are focusing on a new DBS device that can record long-term signals. This is significant, as deep brain signals can usually only be recorded for a few days after the initial implantation. This new device, however, has the potential to record for a much longer time.
They aim to determine if signals from the basal ganglia are stable over time, and if there is a correlation with patient symptoms. They also aim to administer “individualized” DBS, at different patient-specific frequencies. DBS parameters are currently fixed, and this is troublesome for PD patients, whose clinical status fluctuates. Thus, it is important to identify what the brain signals represent and how they change with time, in order to develop adaptive DBS in the future.
Interestingly, the mechanisms of action of DBS are not fully understood. Dr. Chen mentioned that although the initial hypothesis is that DBS inhibits target areas, this is not entirely true. For example, studies have shown that DBS of the thalamus facilitates activity in the thalamus and in the cortex, an area the thalamus projects to. DBS could also inhibit target areas such as the subcortical nucleus, but simultaneously facilitate any signals from the fibers going in and out of the nucleus. Thus, there appears to be a mix of inhibition and activation of target areas and their connected areas. DBS also affects plasticity in the cortex, and suitable timing of pairs of DBS-magnetic brain stimulation can induce plasticity modulation of the brain.
In terms of future directions, Dr. Chen feels that a paradigm for “closed loop or adaptive stimulation” using DBS can be developed. If we can identify the best oscillation pattern for each patient (for example, by recording of basal ganglia signals), it could be possible to create a device that can detect brain signals, and then automatically deliver DBS to change the oscillations to a favorable pattern.
For students interested in a career as a clinician-scientist, Dr. Chen suggests that students should first be exposed to research opportunities and consider the pros and cons of different research areas. Finding a field that they are interested in is more important than looking for a current “hot” area of research. Finally, they should look for the best mentors in the area, and seek out the best place for obtaining training in their chosen area of interest. The role of the clinician-scientist is an exciting one. It allows for a two-way flow of information, with patients providing ideas for research that can be undertaken, and research ideas also feeding into the development of new therapies.