Toward the Treatment of Alzheimer's With Electrical Shocks to the Brain
Deep brain stimulation, currently used to treat tremors, may one day be able to preserve and restore memories.
What would you think if I told you I was going to shock your brain with electricity? You might first have a flashback to Jack Nicholson's "shock shop" in One Flew Over the Cuckoo's Nest or to a crazed Dr. Frankenstein energizing his new creation. But those tales are fiction. In reality, we have harnessed electricity to treat a variety of brain disorders. Much like 70 years ago, when we educated people that when it came to cooking, electricity was their best friend, we are beginning to explore the many benefits of stimulating the deeper parts of the brain with electricity.
Last week, I taught second-year medical students how to perform a neurologic examination. I always enjoy this part of the year, since the medical students are waist-deep in course work and hungry to see a real patient. Our patient had a long history of an essential tremor. When he tried to hold his arms straight out in front of him, his arms and hands moved wildly up and down. It was dramatic. He couldn't bring a glass of water to his lips without soaking himself or anyone within a few feet. It took him 30 minutes to button his shirt. Medications didn't help him, and his degree of disability depressed him.
As I told the students about his operation six years prior, he slowly held a small device that looked like a TV remote control over his chest to turn on the small electrical current at the tip of the wires deep inside his brain. He once again slowly raised his hands, and this time, they were rock solid. Not a tremor, not even a wiggle. The initial collective gasp of the students was followed by a universal exclamation: "Wow." This was why they were becoming physicians -- to change people's lives. It looked like magic, to just flip a switch and change a life. But, this man's "miracle" was the end result of many years of research.
The next day my eye caught a headline on CBS News that read, "Electric brain stimulation may treat Alzheimer's." This is exciting news. Deep brain stimulation (DBS) is highly effective for the treatment of Parkinson's disease, essential tremor, and dystonia. Currently, we're also studying its effect on people with depression, obsessive-compulsive disorder, chronic pain, and obesity. However, the ability to alter the course of Alzheimer's disease would change the lives of tens of millions of people and their families.
***
So, if DBS is such a "miracle worker," what is it really, and how does it work? Clinical trials that placed stimulating wires (electrodes) deep in the brain to control abnormal movements started in the 1980s and were first approved for clinical use in the United States in 1997. The actual procedure is fascinating. The patient is awake throughout most of the procedure so that they can supply feedback on how they feel and the surgeon can see the results of the stimulation on any abnormal movements. Before the surgery begins, a stereotactic frame is screwed into the skull under local anesthesia. It is not as bad as it sounds -- the patient experiences little to no pain. With the frame in place, the surgeon performs an MRI scan, which allows him to calculate within 1mm where he should place the wire deep inside the brain. The patient is briefly put to sleep, and the surgeon drills a small hole on each side of the skull.
The brain itself does not feel pain, so with the patient awake and with the guidance system of the frame attached to the skull, the surgeon passes a small wire with a stimulating electrode at its tip precisely to the desired location. The stimulator attaches to the wire and the wire is positioned so that the patient obtains the desired response without side effects. The hardware is then secured to the skull and the small battery powered implanted pulse generator (IPG) is placed under the skin just below the collarbone. The patient turns the stimulator on and off using a small controller that they place over their skin above the IPG.
Typically, the doctor doesn't turn on the stimulator for 2 to 4 weeks, so everything can heal. The physician "programs" the device to deliver the precise type of electric stimulation by placing another device over the skin and IPG. It may take several months and programming trials to get the desired effects.
***
To be truthful, we are not totally certain how DBS works, but it does help if you understand a few basic facts about the brain. It is simplistic to think that right side of the brain only controls the left side of the body and vice versa. The brain is a complicated collection of neural "networks" that connect distant areas of the brain. Imagine that you are sitting in your air-conditioned office on a warm summer day. The lights, AC, computers and elevators all hum along without a glitch. You hear a light rain hitting the windows, but ten miles away a lightning bolt strikes the relay transformers on the power grid. Your computer blinks off, and suddenly you realize that all the power is gone. Nothing happened at your office that would have cut the power, but since you are on the same power grid as where the lightning struck, all your services shut down. The same thing can happen in your brain.
Think about moving your right arm. There are cells on the left side of the brain that make the actual movement happen, but through a series of networks and connections throughout the brain there are other cells and structures that ensure that your arm moves accurately and smoothly when it reaches for a glass of water and brings it to your lips. To treat the tremors that prevented our patient from drinking his glass of water, the stimulating wires were placed in a small almond sized structure called the thalamus. It acts as a hub and connects the many axons that travel throughout the brain. In this case, the stimulation may keep certain cells from firing (that is, inhibit the cells). But with other diseases, like Alzheimer's, we may want to stimulate specific groups of cells to make them more active. Stimulating different parts of the brain produces different results.
***
The use of DBS for essential tremor and Parkinson's disease has become routine in the United States and Europe, improving the lives of over 100,000 people. In addition to these uses, like I mentioned before, new studies explore the use of DBS for depression, obsessive-compulsive disorder, obesity, chronic pain, and Alzheimer's disease (AD). Like so many things, the idea to use DBS for the treatment of AD was serendipitous. While studying the use of DBS in obesity, the researchers observed that it produced increased memory. This led first to safety trials and now to clinical trials.
In Parkinson's disease, DBS treats symptoms, but does not alter the progressive nature of the disease. The question with Alzheimer's disease is whether stimulation can both improve a person's memory and alter the course of the disease. With more than 115 million new cases of AD predicted worldwide in the next 40 years, this would be a huge accomplishment. In AD test studies, the stimulating electrodes are placed in the fornix, a major bundle of over one million nerve fibers that carry information concerned with memory. It connects the hippocampus, so named because it looks like a seahorse, with many other areas of the brain. The hippocampus is intimately involved with memory and is one of the first areas involved in Alzheimer's disease. Unlike Parkinson's disease, where the stimulation attempts to inhibit or suppress nerve cells, we want to use DBS for AD to increase neural activity in this memory circuit. Early in AD, specific areas of the brain related to memory show a decreased utilization of glucose, the brain's fuel. We can measure that decrease with a PET brain scan. The brain scans of the patients who received DBS for AD revealed an improved use of glucose in memory areas of the brain that were near the area of stimulation and also in areas that were remote from the area of stimulation.
Research for these sort of things starts slowly. A 2010 study of just 6 patients found that DBS not only caused a reversal of the brain's decreased utilization of glucose, the brain's fuel, but also may have slowed the rate of cognitive decline. There were a few interesting descriptions during the initial stimulations in two patients. One had "a sensation of being in a garden, tending to plants on a sunny day," while another reported "fishing on a boat on a wavy blue colored lake with his sons and catching a large green and white fish." Both episodes were real life occurrences, memories of which were elicited by stimulation of the fornix, deep inside the patients' brains.
We have taken the next step, conducting larger clinical studies of people with mild AD. All of the patients will have a DBS implanted in their fornix. One half of the patients will have the stimulator turned on after 2 weeks while the other half will wait a year. The second group is the "control" group to rule out the possibility of a placebo effect. All of the patients will have brain scans and neuropsychological testing performed on a regular basis.
Ideally, these people's memory and cognitive skills will improve and their disease will progress more slowly than it might otherwise. It will take years to know if DBS will work for AD. But if it works, it will be worth the wait.