One of the most innovative medical developments of the 21st century – deep brain stimulation (DBS) – has allowed doctors to target specific regions of the brain and treat conditions such as dystonia, epilepsy, idiopathic tremor, Parkinson’s disease and obsessive-compulsive disorder. This neurosurgical procedure involves implanting electrodes that generate impulses that control abnormal brain activity. With the growth of deep brain stimulation, those within the medical community have speculated where it might expand next.
Announced in 2022, the ADvance Study II (NCT03622905) evaluates the efficacy and safety of DBS in patients with Alzheimer’s disease (AD), a disease that affects an estimated 6.2 million Americans.1 The double-blind study will run for 4 years for the participants, who will be randomized in a 2:1 ratio to either activate or stop a neurostimulator. DBS for AD will involve the use of an implanted device similar to a pacemaker, with two wires connected that deliver mild electrical pulses directly to the fornix, which has previously been linked to memory and learning.
Allegheny Health Network (AHN) will be one of the trial sites for ADvance II, with efforts led by Donald Whiting, MD, AHN’s chief medical officer and head of its Neurosciences Institute. Whiting sat down to provide context for the innovative study, how it was conducted, and why it differs from traditional DBS research. It also provided context for the previous findings leading up to the trial, the outcome measures observed, and why targeting fornix has great potential.
NeurologyLive®: How was the ADvance II study built?
Donald Whiting, MD: The first thing to know is that this advanced study is a second iteration. The ADvance I’m studying was initially done to look at the safety of deep brain stimulation in the fornix for memory problems in the elderly. In that study, deep brain stimulation was shown to be very safe, just like regular deep brain stimulation is very safe. There were some detectable differences within the hippocampus and then the medial temporal lobe, with stimulation of the fornix suggesting the increased activity we thought there would be.
In addition to improving Alzheimer’s symptoms, it also appears to improve executive function, judgment, and problem-solving, as well as memory itself. ADvance’s initial study showed it was safe and that was in 9 centers – us [AHN] None of them were. This led to the ADvance II study, which is now underway. We are one of 14 centers in that study in the United States and there are many more centers that have been added. There are 8 in Germany and 1 in Canada, I think.
This is the result of a serendipitous discovery by Andres Lozano, MD, PhD, FRCPC, FRSC, FCAHS, in Toronto, who was researching deep brain stimulation for another reason, obesity, and was a little off target and ended up in the basement.2 What they found was that after stimulation of that nasty area, the patient had very strong memories of activities of some sort of distant past. Memories of being on the playground as a child, seeing the bright colors of things around them, and the detailed facial features of people. It was like taking a rheostat on a light bulb and cranking up the power of the memory function and making it brighter. That’s kind of what it was about, which then led to the ADvance study.
ADvance II is a study designed specifically for people with mild Alzheimer’s disease. Not severe, but only mild. Not only do we look at safety, but the group looks at efficacy to make sure it’s beneficial. It looks at patients with stimulation on and off and compares control and active groups. Also, he’ll be looking at a few different frequencies because with deep brain stimulation, the electrode composition, pulse width, frequency, amplitude, all factor into the effect you create with the stimulation. This study is primarily for that group of mild Alzheimer’s patients, and it’s looking for efficacy.
Are there significant differences in how deep brain stimulation is given to these patients compared to other movement disorders? Or how have we used DBS technology previously in the past?
Deep brain stimulation has multiple uses. Basically, where we put it depends on what symptoms we’re trying to treat. In the brain, there are electrical circuits and relay centers. And sometimes the circuits are asynchronous or asynchronous. When they reach the relay center, the pulses are not processed appropriately. For example, for essential tremor, we usually like to place the electrode in the ventral medial nucleus of the thalamus, which is the tremor relay center where the fibers come from. By adjusting those parameters you mentioned, we can realign the circuits. becomes more in sync.
Parkinson’s disease, similarly, to the hypothalamic nucleus. In this case, it’s very similar. For Alzheimer’s disease, the migration pathway is the fornix of memory. This is where we motivate. The location is different, but the procedure is the same. The logic behind it and the science is the same. The other thing that we find when we run different areas of stimulation is that sometimes the typical amplitude or pulse width or frequency, is different for that location and that disease than others. You can’t say “Well, I set the settings to the same activator as they were for Parkinson’s patients, but I didn’t get much benefit.” This is part of the science that we are discovering. What are the correct electrical settings to get the most benefit. We’re doing something similar to obesity and stimulating the hypothalamus. What we found was a significantly different set of settings to be effective in that area than in movement disorders.
How do you decide what the quality outcome measures are, given that this is a relatively unexplored area of research?
It is a hot topic for research. There are a lot of drug companies and researchers looking at different things. Much of the research focuses on plaque, plaque accuracy, predictive biomarkers, [vitamin] B12, a bunch of different things. This is all good, and this research is all good. Plaque researchers are trying to reverse the problem to get an improvement, which is likely toward a cure, while this is more toward improving the symptoms of a chronic disease. With this said, there are 4 main standardized memory tests that are well accepted measures of Alzheimer’s disease and function. All of these tests are used with all patients before, during, and after. When you look at all the different things you experience in a study, it’s a good idea to keep the few constants and variables, because then you know what you’re changing. I’m just a detective. I’m not the lead detective, there are a lot of people who do that. But in this study, we’re looking at standardized tests that everyone accepts to show improvement. All we’re trying to do is improve symptoms rather than cure.
The text has been edited for clarity.