One of the most revolutionary medical advances of the 21st century, deep brain stimulation (DBS) allows clinicians to target specific areas of the brain to treat dystonia, epilepsy, essential tremor, Parkinson’s disease, and obsessive-compulsive disorder. You can now treat conditions such as disability. This neurosurgical procedure involves implanted electrodes that generate impulses that control abnormal brain activity. As DBS grows, people in the medical community speculate on how far DBS may spread next.
The ADvance II study (NCT03622905), published in 2022, will evaluate 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 trial lasted 4 years with participants randomized 2:1 to either turn on or turn off the neurostimulator. DBS in AD uses an implanted device similar to a pacemaker. Attached to this device are two of his wires that deliver gentle electrical pulses directly to the cerebral vault previously associated with memory and learning.
Allegheny Health Network (AHN) will be one of the ADvance II study sites, led by AHN’s Chief Medical Officer and Chair of the Neuroscience Institute, Donald Whiting, M.D., Ph.D. Whiting described the groundbreaking study, how it was conducted, and how it differs from his previous DBS studies. He also discussed previous findings leading up to the trial, the observed outcome measures, and why targeting the fornix holds great potential.
NeurologyLive®: How are ADVance II studies structured?
Donald Whiting, M.D.: The first thing to know is that this ADVance study is the second iteration. The ADvance I am researching was originally done to examine the safety of deep brain stimulation of the cerebral vault for memory impairment in older adults.In that study, regular his DBS was very safe. As you can see, DBS has been shown to be very secure. There were some detectable differences within the median hippocampus and temporal lobes, suggesting that stimulation of the cerebral vault increased activity that was thought to be there.
In addition to improving Alzheimer’s symptoms, it also appears to improve executive function, judgment, problem-solving, and memory itself. [AHN] was not one of them. That led to the ongoing ADvance II study. We are one of 14 centers in the United States participating in that study, with several additional centers. I think there are eight in Germany and one in Canada.
This was the result of a serendipitous discovery by Andres Lozano, MD, PhD, FRCPC, FRSC, FCAHS of Toronto, who was studying deep brain stimulation for obesity for another reason, and was a bit off target in the end. phonics.2 What they found was that, with stimulation of the fornix area, the patient had very intense memories of a type of activity in the distant past. Memories of seeing vivid colors, detailed facial features on people. It was like putting a variable resistor on a light bulb to power up the memory function to make it brighter. That’s kind of what led to the ADvance research.
ADVance II is a study designed specifically for people with mild Alzheimer’s disease. Not severe, but mild. We look not only at safety, but also at efficacy to ensure its benefits. We observe patients with stimulation off and on and compare control and active groups. We also look at several different frequencies for deep brain stimulation, as electrode combinations, pulse widths, frequencies, and amplitudes all affect the effect we create in stimulation. This study is primarily targeting a group of people with mild Alzheimer’s disease, looking for efficacy.
Are there any significant differences in how DBS is administered to these patients compared to other movement disorders, or how have they used DBS in the past?
Deep brain stimulation has multiple uses. Basically, where you put it depends on the condition you’re trying to treat. The brain has circuits and relay centers. Also, the circuit may be asynchronous or not synchronous. When they arrive at the relay center, the impulse has not been properly processed. For example, for essential tremor, electrodes are typically placed in the ventral intermediate nucleus of the thalamus. This is the tremor relay center, where the fibers enter. The circuit can be retuned by adjusting the aforementioned parameters. Be more synchronous.
Similarly, Parkinson’s disease of the subthalamic nucleus. In this case it is very similar. For Alzheimer’s disease, the relay pathway is the memory vault. That’s where we inspire. The location is different, but the steps are the same. The reasoning and science behind it is the same. Another thing we find when manipulating different areas for stimulation is that typical amplitudes or pulse widths or frequencies may differ from others for that location and that disease. You can’t say, “Hmm, I put on the same stimulants as the Parkinson’s, and it didn’t do much.” That part of science that we understand. What is the proper electrical setup for maximum effect? We have done something similar for obesity and hypothalamic stimulation. What we found was a markedly different set of settings that were more effective in that area than the movement disorders.
Given that this is a relatively unexplored area of research, how do you determine a measure of quality results?
A hot topic of research. Many pharmaceutical companies and researchers are looking at different things. Many studies have investigated plaque, plaque resolution, predictive biomarkers, [vitamin] B12, various. It’s all good, and its research is all good. While Plaque researchers aim to improve symptoms of chronic disease, they’re trying to reverse the problem in order to get improvement. . With this, there are four major standard memory his tests for Alzheimer’s disease and well-accepted gauges of function. All of these tests are used before, during and after every patient. It’s a good idea to keep constants and some variables because when you look at all the different things you’re looking at in your study, you’ll know what you’re changing. I’m just one of the investigators. I am not the lead investigator. Many people do research. But this study looks at a standard test that everyone accepts to show improvement. All we are trying to do is alleviate the symptoms, not cure them.
Edited transcript for clarity.