Dr. Zelma Kiss

November 2015


In our fourth installment of the series, we introduce you to Dr. Zelma Kiss.  Dr. Kiss is currently an Associate Professor of Neurosurgery in the Department of Clinical Neuroscience at the University of Calgary.  She is a neurosurgeon and clinician scientist; who not only performs deep brain stimulation, but studies how surgical treatments work in the lab.  Dr. Kiss completed her MD at the University of Ottawa in 1988.  After a surgical internship she moved to Toronto for training in Neurosurgery in 1989.  She won the Van Wagenen fellowship from the American Association of Neurological Surgery to pursue further post-doctoral training in France with Professor Alim-Louis Benabid, the father of deep brain stimulation.


Parkinson Association of Alberta (PA):  Why did you choose to pursue research as it pertains to Parkinson's disease?


Dr. Zelma Kiss (DZK):  The focus of my research is on how deep brain stimulation (DBS) works in several movement disorders, Parkinson's being one of them.  My lab mainly studies the cellular mechanisms of how electrical stimulation alters brain cell activities.


Beyond that, DBS is the biggest advance in Parkinson's research since Levodopa.  There is a 30 year gap between the introduction of Levodopa and DBS; other medications have been beneficial, certainly, but none have been as life changing as DBS has been.  Clearly, it has had a big impact; and as such, the vast majority of surgeries I perform (like DBS) are for patients with Parkinson disease as that is the population who receives the largest benefit.


PA:   How did you become interested in this particular field of research?


DZK:    In the early 90's I was in the lab working on my PhD program and at the time there was a resurgence or re-discovery of an old operation called pallidotomy. (Pallidotomy surgery permanently destroys the globus pallidus in the brain to lessen symptoms of Parkinson's).  Prior to that most of the surgeries we were doing were done utilizing thalamotomy for tremor.  (Thalamotomy surgery destroys part of the thalamus in the brain to block abnormal brain activity that causes tremors).   I had based my entire PhD project on thalamic recordings in humans and when the research on pallidotomy was published in 1993; that became the new standard.  This meant that there was a now a new brain target that my thesis was not related to.  


That same year Professor Alim Benabid did his first stereotactic (ST) and deep brain stimulation surgery for Parkinson disease and targeted the subthalamic nucleus.  I decided fairly early on that this was the most exciting thing that was taking place in the field.  The whole field of functional neurosurgery for Parkinson's and movement disorders was changing from lesioning to DBS.  I saw the tremendous potential and decided that I wanted to undertake extra training with Professor Benabid.  He was leading the charge on this exciting avenue of research.  That is how I ended up becoming very interested in DBS as a tool and trying to understand how and why it actually works.


PA:   Wow, you have a long history with DBS as a treatment option for Parkinson's!  What is the current research question you are trying to address and why?


DZK:    A number of people have done work in Parkinson's and I think we've got a good idea of how DBS works in subthalamic nucleus for Parkinson disease.  The other target area, the globus pallidus, is not so clear.


PA:   How so?


DZK:    In Parkinson disease, if you put an electrode into the globus pallidus (another part of the basal ganglia); you get an immediate effect on dyskinesia.  You can stop the abnormal movements that the Parkinson's drugs produce.  Now, if you put an electrode in the exact same place in a patient with dystonia (a different movement disorder), the effects are NOT immediate; it takes weeks to months to see the benefit.


PA:   That is so interesting!


DZK:    In our lab we've done a thorough job of studying how electrical stimulation in thalamus works to stop tremor.  Again, that is an immediate effect.  You turn it on, you see an effect right away.  In subthalamic nucleus as well you see an effect within minutes.  Globus pallidus is different.  So the question is then what is different about that particular target when we use very similar electrical stimulation?  Clearly, the cells are a little bit different, and the connections are different.  It also does not have a direct route to the motor cortex, whereas the subthalamic nucleus does.  Having a direct feedback system to the primary motor cortex (which controls our movement) is how most scientists believe it works.  The globus pallidus does not have a direct route, it has to go through thalamus.  It has multiple pathways, but no direct one.  That is what my lab is focused on trying to understand; and the long term effect of DBS in animals and prolonged, longer term cellular effect.


PA:   Moving forward, how do you envision your research benefiting the Parkinson's community at large?


DZK:    Research in general benefits all patients...


PA:   Absolutely.


DZK:    In terms of where the field is going; based on the current understanding of how deep brain stimulation works, there are multiple groups trying to optimize or make it better than it is thus far.  One of the ways they they are going about that is using a feedback system.  A closed loop stimulation; essentially turning stimulation on when particular brain patterns of activity are detected by the electrode.  Right now it's an open loop, the stimulator is on all the time, 24 hours a day, seven days a week.  The device gets programmed in the office, the patient goes home and it stays exactly the same.  In the future, the hope is that it will be modulated depending on what the patient is doing.  The ability to record brain activity that is abnormal--severity of rigidity, bradykinesia or whatever aspect of Parkinson disease--and have the system feedback different kinds of stimulation or only turn itself on at the times it is needed.  That is one direction. The other direction would be using different patterns of stimulation.  A colleague of mine in Germany is looking into this.  It is really exciting research where they are actually modulating the brain activity over time with different patterns.


PA:   That sounds incredible, how does it work?


DZK:    Currently electrical stimulation is applied the same as it was back in 1993, high frequency and a constant pattern of activity.  He's developed a system where different patterns are applied through different electrodes and benefits are being seen for days to weeks after the stimulation has been turned off.  A long lasting effect is being produced by studying how stimulation works are the very basic cellular level with these different patterns.  That is the direction the field is going; different patterns and responsive or closed loop stimulation where we record brain activity and then stimulate to suppress the brain activity which we think is abnormal.


PA:   So in theory, this could be an extension of time?  When people qualify for DBS, as I understand it, they "buy" themselves about five to seven years.  Is that true?


DZK:    It s different for everybody.  A subthalamic nucleus stimulation typically improves a patients "off" time by about 60% and their "on" time by less than 10%.  Essentially it smooths out a person's day so that they can reduce their medications and it appears like they were about five years prior.

PA:   Ok then to go back to the direction the field is taking, with this method of reading the activity and applying the pulses, could that extend the length of time DBS worked or not really?


DZK:    Yes, that's ideally what we would like to accomplish.

PA:   What are your thoughts on the future of research in Parkinson disease?  What do you see as a bright spot on the horizon?


DZK:    From a DBS perspective I do think that the responsive stimulation  and the various patterns of stimulation have potential.  I can imagine a time when patients do not need to have their device on all the time; maybe only turn it on every week.  Wouldn't that be great?!  You'd save your battery time and it would "hold" you at that level for a period of time.


I've been disappointed by several things that have happened.  I don't think the brain stem nucleus for gait has turned out to be that useful.  People do continue to study it, and it deserves more study, it just hasn't been a slam dunk.  Both ST and DBS were a slam dunk right away.  The results were obvious and there wasn't really a question that it worked,other gait targets have been disappointing.  The gene studies have been disappointing.  Subthalamic nucleus DBS remains the best option in terms of surgery, the globus pallidus as well.  The option is more appropriate for an older population or the people who have really predominant dyskinesias despite small doses of drugs.  Some people cannot go beyond four pills a day before they are disabled by dyskinesia.  I do think that in the future we have potential in the options that reduce the stimulation but improve the type of stimulation that is applied.


PA:   So then have the lesioning techniques (thalamotomy, pallidotomy, etc) fallen by the wayside now that DBS is at the forefront?


DZK:    Pretty much, because once a lesion is made, it's done; you do not have an option to change it without another surgery or procuedure.  We lived through lesioning from the 1950s through the 1990s and we saw what those targets in the brain nuclei in the basal ganglia can do.  The big advantage of DBS is that it is adjustable without another surgery.  Imagine you've got electrodes in there right now, and five years from now someone comes up with a better stimulation pattern; all you do is replace the battery, you do not have to go back into the brain.


PA:   Because it's physically already there...


DZK:    Correct, for example the company Medtronic actually does have a sensor system that senses brain activity which can be downloaded.  It's experimental right now, but it is a designed product that is available for research purposes right now.  It is recording brain activity, not actually stimulating as a result of the recording, so potentially in the future it could be used as a feedback system.  It could pick up one particular biomarking brain pattern, they call them oscillations, so that when the brain oscillates at a certain pattern it could stimulate only when that pattern appears.  Deep brain stimulation has so many more options than lesioning, because once a lesion is done you cannot change or reverse it afterwards.  You can increase the size of a lesion, but you cannot decrease it; whereas you can always turn a stimulator off.  There is just more flexibility.


PA:   Flexibility and the ability to go back and make relatively non-invasive changes sounds exciting!  What do you enjoy most about your research, and your job in general?


DZK:    Discovering new things!  I think that looking at the results of our brain recordings and doing an experiment in the operating room where we show patients pictures of faces and they respond and we find cells that respond to the emotional component of those facial expressions is exciting.  We are discovering new things in research incrementally, it's not one great big discovery.  That is not the way science typically advances; it is usually these incremental discoveries that add up to something more. 


I love the fact that we were one of the first groups to describe how DBS works in thalamus for tremor and then that became the prevailing wisdom.  It sometimes takes a while for others to catch on.  That is part of the positive in incremental discovery though...others publish similar things afterwards and while on one hand you think "That's what we said five or six years ago" on the other hand an experiment that has similar results is complimentary to what you published earlier.


PA:   Like building blocks?


DZK:    Yes!  I think it is the most exciting part!  I also like the patients.  I like to see patients come back for follow up and see that they are doing well and they are happy.  That is the wonder of being a clinician scientist; you get immediate feedback from your patients AND you get the long-term gratification of adding to the overall knowledge on a subject.  I was trained by Dr. Ron Tasker and he said "If you don't learn something from every patient who walks in your office then you are doing something wrong."

PA:   I would agree; everyone has something to learn and something to teach!  Any parting words of advice for people affected by Parkinson disease?


DZK:    I think that there is hope for the future.  Maybe not a cure in my lifetime, but I do think that there are going to be incremental improvements that do make a difference in the quality of life for patients with Parkinson disease.


And the holy grail is preventing; to be able to obtain an early diagnosis so that you can prevent progression.   I'll leave that to the molecular biologists, but that has been the holy grail for fifteen years now.  I think there is a lot of potential with imaging; a great future for MR Spectroscopy and other PET scanning technologies that could make a difference in early diagnosis and potentially give us the ability to study some disease-modifying therapies.


PA:   I think people can often forget that research doesn't just mean a cause or cure; though clearly those are important.  Research is a large umbrella that covers a lot of different aspects and there are all these incredibly bright minds asking about today.  "What can we do to help you live better today?"  The result is amazing projects and discoveries taking place that cover the quality of life and living well right now aspect of Parkinson disease.  Whether its exercise or a new way to carry out DBS; or even the recent news about re-purposing an existing cancer drug--research covers a really broad spectrum and can mean different things to different people.


What is the best part of being involved in research?


DZK:    I love bringing my students and post docs to talk to patient groups.  I think it is so critical that they gain an appreciation of the patients we are working with and what they are experiencing.  My lab has a completely different approach from others in a way that everybody in my lab comes into the operating room.  They will always come and see patients.  It is the students and the post docs who come up with new ideas, read papers, send them to me and get excited about the filed...all within the context of actually seeing patients.   I have to say that is the best thing about research,,,the students and trainees. 





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