Neurology Central

Expanding the boundaries of deep brain stimulation

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Ever wondered how we could ‘reset’ or ‘repair’ brain function in diseases ranging from Parkinson’s to depression? Kendall Lee and his team at the Mayo Clinic (MN, USA) certainly have.

Neurology Central talked to Dr Lee to find out more about his research in the development of real-time closed-loop deep brain stimulation (DBS) technologies for the treatment of neurological disorders as well as the advantages and need for such innovative technologies.

Can you introduce yourself and tell us a little about your career to date?

I started my medical training in the Medical Sciences Training Program, funded through the United States National Institute of Health (NIH), and went to medical school and graduate school at Yale University (CT, USA). Following this, I studied under David McCormick (Yale University), one of our foremost neuroscientists and a recently elected member of the US National Academy of Sciences, who worked extensively on the functioning of neurotransmitters within the brain.

I then went from Yale to start a neurology residency at Harvard University (MA, USA), but I didn’t complete it. Instead, I decided that what I was really interested in was the human brain, specifically operating on the human brain and helping patients with neurological disorders. However, I also wanted to become a physician scientist looking at some of the fundamental mechanics of how the brain functions. So after two years in neurology I went on to study neurosurgery under the tutelage of Dr David Roberts (Dartmouth College; NH, USA), an expert in stereotactic and neurofunctional neurosurgery. At that time the concept of DBS was just beginning to emerge, and in fact I was the first resident to use DBS with Dr Roberts at Dartmouth, where we were using it to help patients with tremor and Parkinson’s disease.

What first attracted you to DBS research? Was it this exposure to it early on in your career?

Definitely, the first time I saw the surgery I was blown away. It was like ‘seeing the light’. When the Parkinson’s patient was awake they were trembling away but as soon as we turned on the stimulation the trembling disappeared. It was a magical moment that I will never forget. When I saw this, the first thing I thought was ‘how is this working?’ I therefore decided that, given my PhD, I would investigate this, so I spent time stimulating animal brain slices and recording the responses. What I saw was a huge release of neurotransmitters which highlighted to me that electrical stimulation and neurotransmitter release must be linked.

What are your current research focuses?

We have come up with an invention that utilizes this concept that DBS releases neurotransmitters and our idea is to control that release. Current DBS systems use ‘open-loop’ stimulation but what we are doing is measuring, using a state of the art electrochemical technique called Fast-Scan Cyclic Voltammetry (FSCV), how DBS release of neurotransmitters varies in different areas of the brain. We are now inventing new technologies to control neurotransmitter release with the hope that ultimately we can use this for not only current indications of DBS in Parkinson’s, tremor and dystonia, but also for neuropsychiatric disorders and addiction. Ultimately this could really transform how we think about modern medicine as all of the drugs that we use are either agonists or antagonists of the neurotransmitter receptors. If we can directly control those neurotransmitter systems we can help our patients.

Do the technologies you’re developing at the moment improve on the specificity of current technologies?

Yes, this is really a whole new concept. Our current DBS systems are effectively a shotgun approach, but now that we can measure and control the stimulation, it makes it a lot more targeted. As you are stimulating you’re going to alter the course of stimulation so even with a moving target we’re still able to hit. This is real-time closed-loop DBS. We stimulate, we sense, we stimulate again, we sense again and we alternate the stimulation based on the response of the neurotransmitter release. This is real-time, it takes 10 milliseconds, that’s pretty fast!

Are there any other ways real-time closed-loop DBS can be utilized?

Well we’re also working on imaging – how to use imaging technology for the targeting. For example one of our grants through the NIH is to use fMRI for identifying the targets. What we’re now discovering about DBS is that it’s not only to do with the target that you have implanted (the DBS electrode) but also where those fibers are going and how the brain circuit is affected. The human brain is very complex; when you affect one area of circuit it really affects many other nodes in that circuit, so we’re trying to develop a technology to do this in real-time as well. The problem with fMRI is that you get the scan but you have to do a lot of image processing to see that image, we want to see that in real-time. It’s still in its infancy, but I’m excited.

The other technology we’re working on that we’re also very excited about is the sensor component, the biomaterials. So far the sensing for all neurotransmitters has for the most part used carbon-fiber electrodes but now we are engineering Chemical Vapor Deposition (CVD) systems to make diamond electrodes. Diamond is a very exciting biomaterial to use for brain sensors because of its ability to last a long time, its stability and its safety in the human brain. As the diamond itself is an insulator you need to modify it into what is called a boron dope diamond. This changes the chemical structure of the diamond so that it’s a conductive molecule which can be used as a sensory system.

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