Vagus Nerve Stimulation: A Novel Approach to Alzheimer’s

Adjunctive Lecturer, Karolinska Institute

This interview was conducted on November 8, 2006 by Peter Cook

Introduction

The efficacy of vagus nerve stimulation (VNS) for treating refractory epilepsy is well established, and VNS has also shown promise for treatment-resistant depression. Two recent studies conducted by Dr. Magnus Sjogren and colleagues suggest that, at some point, VNS may have a place in treating cognitive decline, specifically in patients with Alzheimer’s disease (AD). Dr. Sjogren, who is affiliated with Sweden’s Karolinska Institute, did his clinical training with brain-lesion patients—many of them with AD—but has since become increasingly focused on clinical research. He was heavily involved in the defining longitudinal studies of mild cognitive impairment (MCI) as well as biomarker research in AD during the 90s. Dr. Sjogren was an associate professor at Gothenburg University in the early 2000s before leaving to join the pharmaceutical industry.

VNS and Cognition

“Throughout the late 90s and early 2000s, evidence for the effects of VNS on cognition continued to mount,” Dr. Sjogren says. “Numerous case reports from both epilepsy and depression patients indicated that VNS might positively impact cognition, and then a double-blind, placebo-controlled study was published in Nature that proved it definitively, as well as showing that the positive effects could be lasting.” A colleague of Dr. Sjogren’s brought the idea of using VNS for AD to Dr Sjogren, and Dr. Sjogren developed the clinical trial pilot study.

VNS for AD: Safety

Dr. Sjogren’s examination of VNS for AD patients was a 2-stage project. “Our first study included 10 patients with mild AD. We received ethical approval, and conducted the study with the features found in clinical trials of AD: measurements of global cognitive function and behavioral and affective measures,” he explains. “Previous evidence showed that VNS enhanced memory function, but we naturally wanted to examine a wider array of cognitive functions.” They investigated the effects of VNS in the probands for 6 months, the main purpose being to assess the safety and feasibility of VNS treatment in this population. “We felt confident the treatment would be safe,” Dr. Sjogren says. “It had already been demonstrated safe in patients with epilepsy and depression, and, indeed, our results indicated that VNS is perfectly safe for AD patients.”

The second stage of the project is ongoing and aims to establish long-term safety of VNS in this population as well as examine possible long-term cognitive effects of the treatment. “We wanted to add 20 patients for the long-term safety phase of these studies,” Dr. Sjogren says, “but ended up with 21 in total on treatment.” At this point, one patient has had treatment for more than 5 years, and the treatment still appears perfectly safe. “Our patients have had some of the same minor adverse events that epilepsy patients with VNS implants have had, such as minor scarring at the sight of the surgery, and intermittent hoarseness of voice, but over all, the VNS has been remarkably well tolerated in our study cohort,” Dr. Sjogren says.

Cognitive Results

“It’s very important to remember that these are open, non-controlled studies,” Dr. Sjogren cautions. “While we are measuring cognition in these patients, we cannot say anything conclusive about what effects (if any) VNS has on these patients’ cognitive processes.” That said, the cognitive results of the studies do show promise. “After 6 months, and also after 1 year, our patients demonstrated signs of cognitive improvement or, at least, slowed cognitive decline,” Dr. Sjogren says. “After 12 months, we still saw cognitive improvement in some patients, but fewer than at 6 months. If I were to speculate, it seems likely that the cognitive improvement was, at least partially, related to the treatment. Of course, we can’t rule out placebo effects, although those generally fade after 2 months.” Although the results cannot be viewed as conclusive evidence that VNS positively impacts cognition in AD patients, they are scientifically interesting, and support the value of further studies on VNS for AD patients. Dr. Sjogren also adds that mood enhancement was observed (although not measured) among the study cohort during treatment.

How VNS Might Impact Cognition

As Dr. Sjogren explains, there are two prevailing theories in the research community on how VNS might impact cognition.

“One widely accepted idea is that cognition is enhanced in relation to level of arousal,” he says. “Historically it was thought that the vagus nerve comprised mostly efferent pathways and was responsible for governing control of the autonomic nervous system, we now know that the majority of the pathways in the vagus nerve are afferents, and thus that a major part of the signal traffic in the nerve is directed towards the brain. Evidence from studies in patients with epilepsy supports this view, showing that VNS increases blood flow in a number of brain areas.”

The second, more speculative theory is that VNS engenders long-term, secondary changes in the brain. “There are ongoing long-term initiatives to study the underlying mechanisms behind the cognitive effects, especially in patients with epilepsy and depression and it is possible that we will look at these effects also in AD patients,” Dr. Sjogren says. “One idea is that VNS impacts neural plasticity.”

Going Forward

“For the time-being, there are no initiatives to study VNS applications for AD patients,” Dr. Sjogren says. “However, our studies have shown that the treatment is safe and feasible, and, although the study was non-controlled, the apparent results on cognition are scientifically interesting, and merit further study.”

Dr. Sjogren suggests that placebo-controlled studies would be instructive. “This can be difficult to set up with an invasive procedure like VNS,” he explains, “but one possibility would be a double-blind study in which you implant the VNS device in all of the patients but delay the start of stimulation in one group of patients for a month or two. This would help us assess possible placebo effects on patient response.”

VNS research is currently focused on depression, but Dr. Sjogren believes that VNS for AD patients, especially those with concomitant treatment-resistant depression, shows promise and will likely, at some point in the future, receive more attention. “Our pilot study was the first step in building an argument for the use of VNS in patients with Alzheimer’s, and, possibly, even using VNS for treating other cognitive disorders as well.”

Reference

Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci. 1999;2(1):94-98.

Disclosure: Dr. Sjogren reports no affiliation with or financial interests in any organization that may pose a conflict of interest.