The Promise-and Pitfalls-of Deep Brain Stimulation for Alzheimer’s

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Could an implanted device that sends subtle pulses of electricity to areas of the brain responsible for memory help delay and even reverse some effects of Alzheimer’s disease (AD)? While most scientists exploring potential treatments and cures for AD are focused on developing new drugs, some researchers believe that a surgical procedure known as deep brain stimulation (DBS) may offer a promising approach to treatment.

DBS alters the behavior of brain circuits, or connections, between neurons and has been shown to be effective in treating certain other neurological conditions; it was originally approved by the U. S. Food and Drug Administration (FDA) to treat Parkinson’s disease in 1997. But it was a serendipitous discovery a decade ago that led researchers to study whether DBS can refresh memory and sharpen cognition in people with AD. While DBS has only been studied in a small number of people with Alzheimer’s-all with mild (early-stage) disease-this surprise finding and other intriguing discoveries have prompted researchers to continue assessing its potential to treat this cognition-robbing condition.

A flood of memories

The inspiration to try DBS as a treatment for AD owes a great deal to a 2008 study by researchers at the University of Toronto (UT). Some animal research had suggested that DBS might be used to promote weight loss by curbing the desire to overeat, so the team offered the therapy to a severely obese man who had been unable to shed weight through conventional methods.

The doctors identified a region of the man’s brain they believed they could stimulate to diminish his appetite. But when they inserted electrodes and tested the stimulation, something unexpected happened: The man reported feeling a sense of dj vu and began recalling experiences he had 30 years earlier. As doctors increased the stimulation level, the man’s memories became more vivid and detailed. In particular, the team found that stimulating his hippocampus-which plays a role in the formation of memories-appeared to trigger these recollections. Moreover, standard tests of the man’s cognitive abilities showed that after receiving DBS, certain aspects of his memory improved significantly, including his ability to learn and recall lists of words.

DBS for early-stage AD

The researchers’ experience with this man persuaded them to investigate DBS’s impact on the brain activity and cognition of a half dozen patients with mild AD. Specifically, they wanted to know whether DBS influences how the brain uses glucose, a form of sugar that is the organ’s main source of energy. In the brains of people with AD, the amount of glucose that is metabolized (or burned as energy) gradually declines as the disease worsens. The researchers also administered mental status tests to determine whether DBS improved the study participants’ memory and mental clarity.

In this study, published in 2010 in the Annals of Neurology, each AD patient received DBS administered to the hippocampus and fornix. The latter is a large bundle of about 1.2 million axons (nerve fibers) that serve as transmission lines for signals in and out of the hippocampus and its surrounding tissue (the medial temporal lobe). Damage to the fornix is known to cause memory loss. Each person received continuous DBS with an imperceptible amount of electricity (3 to 3.5 volts) for 12 months, then underwent positron emission tomography (PET) brain scans.

The scans indicated that DBS stimulated activity in the fornix and increased glucose metabolism in the temporal lobe and a related region involved in memory. In other words, the patients’ brains were burning more glucose, an indication that their neurons were more active and energized. What’s more, the overall rate of decline in cognitive ability after surgery was slower than the pre-surgery rate. However, it appeared that participants whose dementia was less advanced at the outset were most likely to benefit from the treatment.

The ADvance Study is an 18-month trial led by the UT group and researchers at Johns Hopkins. For this study, 42 people (age 48 to 79) with mild AD had DBS systems implanted; the fornix was targeted for continuous stimulation with low-grade electrical pulses (3 to 3.5 volts). Initially, only half of the patients had their devices switched on. The remaining patients served as a comparison group (though at the end of the study their devices were turned on as well).

PET scans obtained at six months showed that DBS significantly increased glucose metabolism, though that did not prove true at 12 months. Overall, mental status testing showed no difference between the “on” and “off” groups after one year. But a closer analysis of the results, reported in 2016 in the Journal of Alzheimer’s Disease, suggested that age influenced the impact of DBS. The 12 participants under age 65 performed poorly in cognitive testing when DBS was turned on, but the other 30 participants, all of whom were 65 or older, showed less decline in cognition over the course of the study if their DBS was turned on compared with those whose device was left off. The authors hypothesize that younger patients may not benefit because early-onset AD (the name given to the condition when it strikes people under age 65) is a more aggressive and severe version of the disease, making it less likely to respond to stimulation.

More research needed

While these studies are promising, keep in mind that they involve small numbers of patients and that the best results were not hypothesized before the study began. Therefore, more research is necessary to better understand whether DBS truly improves symptoms of AD in a subset of people. One concern facing investigators is ensuring that study participants understand the risks involved in DBS (though the therapy appears to be relatively safe) and have the capacity to grant consent to participate in trials. Technical questions need to be resolved, too, such as how much stimulation is safe and effective. (Animal studies suggest that turning up the voltage too high can backfire by worsening memory.)

While there remains much to learn about DBS, this research raises hope that non-drug therapies may one day give doctors a new weapon in the battle against Alzheimer’s.