Cholinergic Deep Brain Stimulation for Memory and Cognitive Disorders

Prof. Christos Constantinidis

Professor of Biomedical Engineering, Neuroscience & Ophthalmology & Visual Sciences, Vanderbilt University

Prof. Christos Constantinidis received his PhD in neuroscience at Johns Hopkins University and later did a postdoctoral fellowship at Yale University. Ever since then the focus of his work was understanding the neural signals from the brain and specifically how the electrical activity of neurons in the brain gives rise to mental phenomena such as working memory, attention or the ability to make thoughts and make decisions. Once he had accumulated this basic understanding of the neural mechanisms of cognitive functions he entered the field of neuromodulation. His focus was on how to improve cognitive function in patients and people who really stand to benefit from it. The programme he has built for the last 5-6 years has focused on using deep brain stimulation as a form of neuromodulation that can improve working memory and quality functions in patients.

Why use Deep Brain Stimulation for cognitive disorders?

Jonathan: Why is it that you decided to use deep brain stimulation? Because I think some people would argue that, well there’s quite a lot of evidence that non-invasive neuromodulation can enhance cognitive performance and when we think about dealing with the pandemic of dementia then arguably non-invasive approaches are much easier from a regulatory perspective and to get to market. So what was it about DBS that made you think this is the paradigm that we should be using to explore this?

Christos: When we started out we had exactly the same thought, that a non-invasive neuromodulatory procedure would likely be a better means of doing that easier and less invasive, involving less risk. However, we discovered that what we have available right now really does not have the spatial resolution and it doesn’t have the specificity that we can gain with deep brain stimulation. That doesn’t preclude that in the future technologies will progress and become much more powerful, allowing us to achieve the same goals. So in a way what we’re doing now with deep brain stimulation, paves the way for identifying the targets and parameters of stimulation that may be achieved with other mentalities as well in the future. But to really get some conclusive and decisive results that saw the viability of this approach, we felt that we had to start with this more invasive but at the same time more precise means of stimulation.

Do we understand enough about cognition to develop DBS-based therapeutics?

When we entered the field of neuromodulation and deep brain stimulation in my lab, we thought that the most urgent and important model that we needed to address was Alzheimer’s disease, a degenerative condition for which there’s no treatment. There’s no way to halt the aetiology of the disease and is also not very well understood. A diagnosis of Alzheimer’s today means that this patient will inexorably decline and we have no means of halting that. So that was really the area that we first thought that we needed to address.

A lot of research effort has been devoted to Alzheimer’s disease and a lot of bright and capable scientists have worked in this area for a long period of time and the results have frankly been disappointed. I don’t want to offend my colleagues that work in this field but we really do not have a treatment. The pathologies that are well-identified and well-understood in Alzheimer’s disease,  the accumulation of onward blacks and entangles looked like very logical targets for the development of drugs that will clear them or stop their production and yet there has been a lot of disappointments and a lot of dead ends. We really don’t have any grounds basically that can cure the disease or even stop the progression of cognitive decline. So at some level, we understand well the circuits that mediate that, but obviously, there’s a lot of depth that we don’t yet understand.

For the type of neuromodulation that we’re looking at we feel that we have a good enough understanding of the basic system and we can address it. So the area that our DBS paradigm has focused on is the cholinergic forebrain and specifically the nucleus basalis meynert, which is the source of acetylcholine in the neocortex of the human brain. So by targeting this area, we have in essence the ability to turn the switch on and off of acetylcholine released in the brain and there’s strong evidence that in Alzheimer’s disease one of the first areas of degeneration is, in fact, the basal forebrain.

So if we’re able to artificially stimulate this area I think we have two mechanistic benefits at the same time. Firstly, we release acetylcholine, which is essential for cognitive functions it’s basically the volume control of the brain that Alzheimer’s patients lose, and frontline medication in Alzheimer’s patients like the nepazil does precisely that, it enhances the action of acetylcholine. However, we can do that endogenously which has many benefits. Number one, we can release more acetylcholine, we have more activity of the cholinergic system and number two, there is at least some indirect evidence that the basal forebrain is part of the pathophysiology of what’s happened. So when this area degenerates, then all the downstream targets, all the areas that normally receive innervation from visual probate, begin to atrophy and degenerate themselves.

I oversimplified the system which is much more complex, but I think at the basic level we have some idea of the circuit that we’re targeting and we have reasons to believe that by focusing neuromodulation there, we can stop the progression of the disease and at the same time offer cognitive improvement to these patients that will otherwise have no effective treatment.

How good are current drug treatments for dementias such as Alzheimer’s?

Our frontline treatment of Alzheimer’s disease today are cholinesterase inhibitors, like Aricept for example, which do not provide treatment for the condition, but they delay the progression of cognitive symptoms. So they offer some relief from cognitive symptoms but this is temporary, in a period of a few months at best. Then the effectiveness of this medication starts to decline and there are several reasons for that. So there are two downsides to giving this drug systemically. Number one, the acetylcholine receptors exist everywhere in the body, so to safely administer the drug cannot be very high because they’re going to be peripheral side effects, therefore we’re limiting the doses. Secondly when you give a drug systemically then you have an action of this drug 24 hours a day, whether the brain needs it or not, which is also a downside. And thirdly by flooding the system indiscriminately with this drug you build some tolerance and it becomes less and less effective. Neuromodulation or deep brain stimulation circumvents all of these problems.

Are patients willing to try an experimental therapy to treat their cognitive impairment?

First of all, we can time the stimulation, so we can only apply stimulation for a few hours a day during waking hours when we want to have a higher alertness. Secondly, acetylcholine is only one part of this endogenous system that projects from the basal forebrain. There is evidence that a different type of neurons, GABA neurons, also project and this cannot be captured by this drug. So by stimulating the source of acetylcholine we have the natural release with all the types of neurotransmitters that normally are released simultaneously with acetylcholine. So that’s a more natural way of stimulating the effects of acetylcholine in the brain.

We were very encouraged and excited when we saw in our initial experiments in animal models that by doing this stimulation the effects of neuromodulation do not plateau and decline but in fact, they remain steady and over the period that we tracked they accrued and the stimulation continues to be effective. So the effect of stimulation is to provide the stimulation of the rest of the entire mantle of the cerebral cortex that normally gets activated by the release of acetylcholine and prevent that degeneration of circuits that may happen when you have this loss of cholinergic stimulation. But we have reasons to believe that this causes some long-term plasticity. It causes circuits to become more active and the action of acetylcholine becomes more effective with time and it’s these late effects basically that I think is the most promising aspect of neuromodulation targeting the cholinergic forebrain. That’s really where we stand now and that’s where our understanding is.

How can we utilise the data we receive from patients who have already undergone DBS surgery for patients with cognitive disorders?

First of all, out of the thousands of patients that have been implanted with these electrodes, there are some electrodes that have missed their target that. In fact, there are patients today as we speak that have electrodes near or at the nucleus basalis. As a matter of fact, some of the initial clinical studies were done precisely in patients that by accident had subthalamic or basal ganglia stimulation. I think there have been some secondary studies that have looked at cognitive defects, I don’t want to venture into anything in this field that it’s not the core of my expertise, but my understanding is that generally, these have not been positive. So just the stimulation at these high-frequency parameters at least of the basal ganglia, generally do not translate into cognitive improvement. However, this is something we’re very interested in.

In fact, we, in collaboration with two groups of clinicians at Vanderbilt and at the Medical College of Georgia, want to find patients that have already been implanted with electrodes near our intended targets, see if we can approach them and see if we can apply experimentally this protocol of intermittent stimulation and see some secondary measures of improvement of cognitive metabolism. Perhaps through PET imaging, we can see that this is really a viable approach in human beings without having to do anything invasive in new patients. So I think that’s a very promising approach that we can explain.

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