Nerve stimulation for severe depression changes brain function

For nearly a decade, doctors have used implanted electronic stimulators to treat severe depression in people who don’t respond to standard antidepressant therapy.

Now, preliminary brain scan studies conducted by researchers at Washington University School of Medicine in St. Louis are beginning to reveal the processes occurring in the brain during stimulation and may provide some clues about how the device improves depression. They found that vagus nerve stimulation brings about changes in brain metabolism weeks or even months before patients begin to feel better.

The findings will appear in an upcoming issue of the journal Brain Stimulation and are now available online.

“Previous studies involving large numbers of people have demonstrated that many with treatment-resistant depression improve with vagus nerve stimulation,” said first author Charles R. Conway, MD, associate professor of psychiatry. “But little is known about how this stimulation works to relieve depression. We focused on specific brain regions known to be connected to depression.”

Conway’s team followed 13 people with treatment-resistant depression. Their symptoms had not improved after many months of treatment with as many as five different antidepressant medications. Most had been depressed for at least two years, but some patients had been clinically depressed for more than 20 years.

All of the participants had surgery to insert a device to electronically stimulate the left vagus nerve, which runs down the side of the body from the brainstem to the abdomen. Once activated, the device delivers a 30-second electronic stimulus to the vagus nerve every five minutes.

To establish the nature of the treatment’s effects on brain activity, the researchers performed positron emission tomography (PET) brain imaging before the initiation of stimulation, and again three and 12 months after stimulation had begun.

Eventually, nine of the 13 subjects experienced improvements in depression with the treatment. However, in most cases it took several months for improvement to occur.

Remarkably, in those who responded, the scans showed significant changes in brain metabolism following three months of stimulation, which typically preceded improvements in symptoms of depression by several months.

“We saw very large changes in brain metabolism occurring far in advance of any improvement in mood,” Conway said. “It’s almost as if there’s an adaptive process that occurs. First, the brain begins to function differently. Then, the patient’s mood begins to improve.”

Although the patients remained on antidepressants for several months after their stimulators were implanted, Conway says many of those who responded to the device eventually were able to stop taking medication.

“Sometimes the antidepressant drugs work in concert with the stimulator, but it appears to us that when people get better, it is the vagus nerve stimulator that is doing the heavy lifting,” Conway explained. “Stimulation seems to be responsible for most of the improvement we see.”

Additionally, the PET scans demonstrated that structures deeper in the brain also begin to change several months after nerve stimulation begins. Many of those structures have high concentrations of brain cells that release dopamine, a neurotransmitter that helps control the brain’s reward and pleasure centers and also helps regulate emotional responses.

There is a consensus forming among depression researchers that problems in dopamine pathways may be particularly important in treatment-resistant depression, according to Conway. And he said the finding that vagus nerve stimulators influence those pathways may explain why the therapy can help and why, when it works, its effects are not transient. Patients who respond to vagus nerve stimulation tend to get better and stay better.

“We hypothesized that something significant had to be occurring in the brain, and our research seems to back that up,” he said.

Research Suggests Link Between Elevated Blood Sugar, Alzheimer’s Risk

A new University of Arizona study, published in the journal Neurology, suggests a possible link between elevated blood sugar levels and risk for developing Alzheimer’s disease.

About 5 percent of men and women, ages 65 to 74, have Alzheimer’s disease, and it is estimated that nearly half of those age 85 and older may have the disease, according to the U.S. Centers for Disease Control and Prevention. Among the known factors that contribute to the disease are age and genetics. Scientists also think that high blood pressure, high cholesterol and diabetes may increase risk.

Although the link between diabetes and Alzheimer’s has been studied, UA researchers wondered if elevated blood sugar levels in non-diabetic individuals also might indicate a higher risk for developing Alzheimer’s disease.

"There have been studies that have linked diabetes to Alzheimer’s disease as a risk factor," said Alfred Kaszniak, UA professor of psychology and a co-author on the study. "What was not known when we began this work is whether that risk was only at levels of blood sugar that qualify for diagnoses of diabetes, or in the borderline or pre-diabetic range, or would we also see a relationship across the so-called normal range of blood glucose?"

The researchers used fluorodeoxyglucose (18F) positron electron tomography, or FDG PET, a medical imaging technique that produces three-dimensional images of metabolic activity in the brain. Fasting serum glucose levels – blood sugar levels following several hours of not eating – are routinely acquired as part of the FDG PET protocol.

"When compared to those without the disease, Alzheimer’s disease patients demonstrate a pattern of reduced brain metabolism in particular brain regions," explained Christine Burns, lead author on the study and a UA pre-doctoral student in psychology. "What we show is an association between elevated fasting serum glucose levels and a similar pattern of reduced metabolism in these same AD-related brain regions in cognitively healthy adults."

The researchers studied data on 124 cognitively normal, non-diabetic adults with a family history of Alzheimer’s disease. The individuals, who ranged in age from 47 to 68, were among participants in a larger study, led by Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, looking at a variety of Alzheimer’s risk factors, including genetic risk. 

The link between high blood sugar and reduced brain metabolism existed regardless of whether individuals carried the Apolipoprotein E4 gene variant, an established risk factor for the development of Alzheimer’s disease.   

In addition to suggesting a link between elevated blood sugar levels and Alzheimer’s risk in non-diabetic individuals, the study also shows promise for the use of brain imaging techniques like PET in identifying Alzheimer’s risk and developing early preventative interventions, researchers say.

"Right now, if you want to develop a drug or evaluate some other kind of a preventive measure for Alzheimer’s disease, the labor and expense is prohibitive," Kaszniak said. "If you recruit people who may be at some risk, but are 20 years away from developing signs of the illness, what drug company or governmental agency is going to fund research that follows people for 20 years to see whether something is effective in prevention?

"However, if you have a biologic marker, it suggests what areas you should really focus on in those very expensive longitudinal studies," he said.

Burns said she hopes the findings will inform ongoing work designed to help develop early Alzheimer’s interventions.

"A lot of valuable research is focused on treatment and slowing decline in Alzheimer’s patients," she said. "I’m interested in complementing this work with interventions that can be implemented earlier on, perhaps at middle age."