Deep Brain Stimulation | Adaptive Neuromodulation

Dr Ro'ee Gilron

Starr Lab at the Department of Neurosurgery, UCSF

Dr Ro’ee Gilron is a postdoc in the Starr Lab at UCSF. He conducted his research at the epilepsy monitoring unit and he is specifically interested in the mechanisms underlying the therapeutic benefits of Deep Brain Stimulation (DBS) for movement disorders. He is currently developing adaptive DBS for the control of tremors, studying the factors underlying the variability of chronic long term recordings from DBS and developing software for the next generation of DBS devices.

Deep Brain Stimulation

as a Treatment for Brain Disease

As Dr De Ridder said in one of your previous talks, a motor disorder, is usually associated with tremor, a hyperkinetic symptom where you move excessively. There’s also dyskinesia, these unwanted wiggly movements, and a lot of hypokinetic symptoms, where you are moving less than you want to, or you can freeze in the middle of walking and your movement becomes very slow. 

DBS is not the first treatment that these patients try. Usually, they will take some form of dopamine replacement, because the disease starts from a tiny nucleus in the brain, where these dopaminergic neurons essentially die. That has wide-ranging effects throughout the brain, which we now think of as Parkinson’s and network disorders. We can initially really effectively treat it with medications, which essentially help us replace the dopamine, but starting in the 50s and 60s, people discovered in a series of experiments that you could actually take out this diseased area of the brain, causing potentially pathological oscillations. This area was surgically removed or lesioned, and that vastly improved the parkinsonian symptoms in patients where the medications became less effective.

Then in the early 90s, people (one of the pioneers was Dr Hagai Bergman who was also in Israel) had this idea of instead of irreversibly taking this small area in the brain and lesioning it or destroying it, you could put a little electrode in there and create a reversible lesion. Meaning that you could fine-tune that small area in the brain and just the surgery itself being exposed to that.

Dr Star’s lab is kind of mind-boggling. You are trying to hit a tiny almond-shaped nucleus; in most cases the subthalamic nucleus, which is deep in the brain and connected to many other structures in the brain through a tangle of blood vessels and not only you have to have this nucleus, but you have to hit a very specific part of it to have a very effective treatment. That’s Deep Brain Stimulation which has been going on since the 1990s.

The shocking moment for me is when [...]
you flip a switch and the tremor is gone.

There have been upwards of 200,000 – 300,000 patients by now worldwide that have received this therapy. It is very effective and remarkable that this crude stimulation could vastly improve symptom control for a lot of patients. Another shocking moment for me was seeing how improved that is when I was sitting in the clinic with a patient after the surgery and after the neurologist has programmed and tuned their stimulation precisely where it needs to be, in the right contact and frequency, I was seeing someone that had an uncontrollable tremor, and you flip a switch, and it’s gone. It is literally within a few seconds, and that’s remarkable.

Why Does Brain Stimulation Work at All?

I think there’s been a lot of people that study this to a much greater degree than I do, but I believe that to a large extent, we’re thinking more and more of these disorders as oscillopathy. Essentially, if you think of your brain as being a symphony with 86 billion neurons, they all need to talk to each other perfectly at the right time. And as in a lot of these disorders, like epilepsy or Parkinson’s, you can have one instrument, perhaps you can think of a drum that is drowning out everyone else. So someone is banging this drum really hard.

And I believe that in a lot of these disorders, the reason this crude stimulation it’s so effective is that you can target that one area in the brain and tamp that down to recover normal communication. I think Dr De Ridder talked about the difference between enhancement and changing of stimulation in the previous series and that’s a very apt analogy. If you’re trying to prevent someone from speaking, that’s a lot easier when it comes to these crude electrodes compared to fine-tuning a specific way to produce an experience, for example.

That being said, I believe we are also very lucky in movement disorders because there are now trials trying to adapt neuromodulation to a lot of other disorders, and it’s a lot more difficult to do.

Why Do We Need Adaptive Deep Brain Stimulation?

Deep Brain Stimulation, is extremely effective for Parkinson’s patients, but not for all. There are some limitations. One of the problems is that these patients, specifically in the case of Parkinson’s, fluctuate throughout the day; so their symptoms are not always the same. It’s not that they always have tremors or they are always slowly moving. They take medication to help with these symptoms and the medication is less effective.

Each dose gives them benefit for less time and the transition between being medicated and not medicated is also pretty extreme. These fluctuations continue after Deep Brain Stimulation, even though it helps with many of their symptoms, and sometimes, they can be so severe that it can interfere with therapy. So they are not getting the most effective dose of stimulation because these fluctuations may limit them.

For example, if they are (patients) very slow, we (clinicians) can give them stimulation to make them a lot faster, but then their medication will kick in and it interacts with these medications, and along with the stimulation, they both have an interaction on the brain: one chemical side of the brain with the medication, the electrical side with the stimulation. As a result, they can produce unwanted side effects, like extreme wiggly movements. Another big aspect that our lab and others at UCSF are looking into is other ways of how Deep Brain Stimulation is not effective for some of the parkinsonian symptoms in particular.

Parkinson’s is known as a motor disorder, but there are many other aspects in the motor behaviour that aren’t well-controlled by Parkinson’s, freezing of gait is a good example, where they walk through a doorway and just freeze, and that’s not well-controlled with Deep Brain Stimulation. There’s also a whole host of non-motive symptoms, like issues of motivation, anxiety, depression that are associated with Parkinson’s. Sometimes those can be even more debilitating, and the small nucleus that we’re hitting actually is associated with all of these symptoms. It is possible that with smarter Deep Brain Stimulation, we can try and interact with some of these other subsystems and address either side effects or other symptoms that aren’t now well-controlled with Deep Brain Stimulation.

How Are the Patients Involved

in the Research for Neuromodulation?

I think the patients are the real heroes here. We work with a very small number of patients in our area, and it’s a very tight relationship. For ethical reasons they can’t be compensated for this, so the patients are volunteering for this work and are extremely dedicated to the data collection. The amount of data they’ve collected is staggering and is likely more at this point than the entire field combined, so we’re learning a lot from what they’re doing. 

We also get to know the patients well, usually, we have a patient appreciation dinner where we share our research every year and get to meet the patients. We had to do it over zoom this year because of covid, but it was really lovely to see everyone. One of the happy accidents of the work this year is that all was meant to be remote because it’s meant to test out neuromodulation in the patient’s home in the real world to drive this forward. So by doing that, essentially, we were able to keep working despite covid and do everything remote over zoom.

What breakthroughs are we expecting

in the field of neuromodulation in the next 5 to 10 years?

I believe we will see a lot more of these sensing and stimulation devices. I am hoping that this will be transformational for other disorders. So, for the neuropsychiatric disorders where there’s so much need, I’m hoping we get a big breakthrough there because I think it’s long overdue, and that’s one of the most areas where there’s the most unmet need.

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