Posts Tagged ‘deep-brain-stimulation’


The dentate gyrus of a mouse that received deep brain stimulation, with cell nuclei in blue and expression of the gene c-Fos in red.

By Shawna Williams

Even as patients with Parkinson’s disease, obsessive-compulsive disorder, and other conditions turn to deep brain stimulation (DBS) to keep their symptoms in check, it’s been unclear to scientists why the therapy works. Now, researchers in Texas report that in mice, the treatment dials the activity of hundreds of genes up or down in brain cells. Their results, published in eLife March 23, hint that DBS’s use could be expanded to include improving learning and memory in people with intellectual disabilities.

“The paper is very well done. . . . It’s really a rigorous study,” says Zhaolan “Joe” Zhou, a neuroscientist at the University of Pennsylvania’s Perelman School of Medicine who reviewed the paper for eLife. Now that the genes and pathways DBS affects are known, researchers can home in on ways to improve the treatment, or perhaps combine the therapy with pharmacological approaches to boost its effect, he says.

In DBS, two electrodes are surgically implanted in a patient’s brain (the area depends on the disorder being treated), and connected to generators that are placed in the chest. Gentle pulses of electricity are then passed continuously through the electrodes. The treatment reduces motor symptoms in many people with Parkinson’s, and allows some patients to reduce their use of medications, but it does not eliminate symptoms or slow the disease’s progression.

In addition to its use in movement disorders, DBS is being explored as a potential therapy for a range of other brain-related disorders. For instance, as a way to boost learning and memory in people with Alzheimer’s disease, researchers are looking into stimulating the fimbria-fornix, a brain region thought to regulate the activity of the memory-storing hippocampus.

Such studies made Huda Zoghbi, a neurogeneticist at Baylor College of Medicine, wonder what effect DBS might have on learning- and memory-related disorders that strike earlier in life. “We rationalized that maybe in Alzheimer’s, many of the neurons are already gone, but perhaps in a healthier brain, like that of a Rett syndrome model, we can test the idea if stimulation of the fornix can improve learning and memory,” she explains. Rett syndrome, a genetic disease that almost exclusively strikes girls, includes intellectual disability, autism-like deficits in social interactions, and a loss of motor function. Several years ago, Zoghbi and colleagues tried zapping the fimbria-fornix, a C-shape bundle of nerves adjacent to the hippocampus in the brain, in mouse models of Rett syndrome. Published in 2015, their results showed that after two weeks of daily, one-hour DBS sessions, the mice with an intellectual disability performed like their peers without the disorder on a range of hippocampus-dependent tasks.

“We were struck that everything became indistinguishable after deep brain stimulation from a baseline normal,” Zoghbi says. This prompted her team to ask, “How does it work at a molecular level?” The answer, she thought, could determine whether DBS of the fimbria-fornix has the potential to serve as a multipurpose tool, treating not just Rett syndrome but other childhood-onset intellectual disabilities with a variety of causes. “It’s going to be really tough, perhaps, to solve these diseases one gene at a time, so that learning can be corrected,” she says. “You could eventually consider an intervention that can be broadly applicable, irrespective of the molecular cause of the defect.”

For the latest study, the research team analyzed baseline differences in gene activity between mice with and without the Rett syndrome–like condition in a part of the hippocampus called the dentate gyrus. They also treated the mice with the intellectual disability once with 45 minutes of DBS. Of the many genes with marked differences in initial activity between the two groups of mice, one-quarter (39 genes) became normal in the Rett mice after treatment, they report.

Zoghbi’s group also tested the effects of DBS in normal mice; in addition to changing the activity levels of thousands of genes, the researchers found, the treatment prompted alternative splicing of the RNA copies of other genes, which would result in differences in the resulting proteins. Many of the genes affected by the alternative splicing are known to be involved in the growth of new neurons or in maintaining the synapses through which brain cells communicate. In the 2015 study, the group had found that DBS enhances some hippocampus-related abilities in wildtype mice, such as spatial learning.

For hints as to whether DBS might have the potential to treat intellectual disabilities other than Rett syndrome, the researchers compared their list of genes whose activity levels changed after DBS in normal mice with existing data on genes known to have abnormal expression levels in mouse models of several such disorders. As with Rett syndrome, DBS in wildtype mice altered the activity levels of about one-quarter of the genes involved in each of the disorders.

The fact that a short period of stimulation had such profound effects on gene expression is interesting, says Svjetlana Miocinovic, a movement-disorders neurologist at Emory University who was not involved in the study. Most research on the mechanism of DBS has focused on changes it induces in the electrical or physical properties of the brain, she tells The Scientist. “I think this kind of study, where they actually look at the molecular environment in these neurons that are exposed to stimulation . . . is really the way to figure out what exactly is going on and how is that neural plasticity accomplished.”

Now that they have a way to measure such molecular effects, Zoghbi and her collaborators plan to optimize DBS for models of intellectual disabilities—figuring out how long the current needs to be on, for example, and how often. Another question they’d like to address is whether stimulating other brain areas in addition to the fimbria-fornix could add to the benefits seen in the mice.

Zoghbi emphasizes that even if DBS turns out to be safe and effective for children with Rett syndrome, it won’t be a silver bullet, because patients will have missed out on some important developmental milestones. “To really get the full benefit,” she says, “we’re going to have to combine any intervention with intensive physical and behavioral therapy.”

A. Pohodish et al., “Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity,” eLife, doi:10.7554/eLife.34031, 2018.

https://www.the-scientist.com/?articles.view/articleNo/54581/title/Deep-Brain-Stimulation-Affects-the-Activity-of-Hundreds-of-Genes/&utm_campaign=TS_DAILY%20NEWSLETTER_2018&utm_source=hs_email&utm_medium=email&utm_content=62919749&_hsenc=p2ANqtz-_Wc4T-kVW-WjClgnxcSv-OaWmpr8r7DtQJQRRztFWWATkUzGmgHVi5RLo74kNAO-J2872OymH-_uX0WKTVquRF4v7QAw&_hsmi=62919749

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It seems simple: Walk to the refrigerator and grab a drink.

But Brett Larsen, 37, opens the door gingerly — peeks in — closes it, opens it, closes it and opens it again. This goes on for several minutes.

When he finally gets out a bottle of soda, he places his thumb and index finger on the cap, just so. Twists it open. Twists it closed. Twists it open.

“Just think about any movement that you have during the course of a day — closing a door or flushing the toilet — over and over and over,” said Michele Larsen, Brett’s mother.

“I cannot tell you the number of things we’ve had to replace for being broken because they’ve been used so many times.”

At 12, Larsen was diagnosed with obsessive-compulsive disorder, or OCD. It causes anxiety, which grips him so tightly that his only relief is repetition. It manifests in the smallest of tasks: taking a shower, putting on his shoes, walking through a doorway.

There are days when Larsen cannot leave the house.

“I can only imagine how difficult that is to live with that every single living waking moment of your life,” said Dr. Gerald Maguire, Larsen’s psychiatrist.

In a last-ditch effort to relieve his symptoms, Larsen decided to undergo deep brain stimulation. Electrodes were implanted in his brain, nestled near the striatum, an area thought to be responsible for deep, primitive emotions such as anxiety and fear.

Brett’s OCD trigger

Brett says his obsessions and compulsions began when he was 10, after his father died.

“I started worrying a lot about my family and loved ones dying or something bad happening to them,” he said. “I just got the thought in my head that if I switch the light off a certain amount of times, maybe I could control it somehow.

“Then I just kept doing it, and it got worse and worse.”

“Being OCD” has become a cultural catchphrase, but for people with the actual disorder, life can feel like a broken record. With OCD, the normal impulse to go back and check if you turned off the stove, or whether you left the lights on, becomes part of a crippling ritual.

The disease hijacked Larsen’s life (he cannot hold down a job and rarely sees friends); his personality (he can be stone-faced, with only glimpses of a slight smile); and his speech (a stuttering-like condition causes his speaking to be halting and labored.)

He spent the past two decades trying everything: multiple medication combinations, cognitive behavioral therapy, cross-country visits to specialists, even hospitalization.

Nothing could quell the anxiety churning inside him.

“This is not something that you consider first line for patients because this is invasive,” said Maguire, chair of psychiatry and neuroscience at the University of California Riverside medical school, and part of the team evaluating whether Larsen was a good candidate for deep brain stimulation. “It’s reserved for those patients when the standard therapies, the talk therapies, the medication therapies have failed.”

Deep brain stimulation is an experimental intervention, most commonly used among patients with nervous system disorders such as essential tremor, dystonia or Parkinson’s disease. In rare cases, it has been used for patients with intractable depression and OCD.

The electrodes alter the electrical field around regions of the brain thought to influence disease — in some cases amplifying it, in others dampening it — in hopes of relieving symptoms, said Dr. Frank Hsu, professor and chair of the department of neurosurgery at University of California, Irvine.

Hsu says stimulating the brain has worked with several OCD patients, but that the precise mechanism is not well understood.

The procedure is not innocuous: It involves a small risk of bleeding in the brain, stroke and infection. A battery pack embedded under the skin keeps the electrical current coursing to the brain, but each time the batteries run out, another surgical procedure is required.

‘I feel like laughing’

As doctors navigated Larsen’s brain tissue in the operating room — stimulating different areas to determine where to focus the electrical current — Larsen began to feel his fear fade.

At one point he began beaming, then giggling. It was an uncharacteristic light moment for someone usually gripped by anxiety.

In response to Larsen’s laughter, a staff member in the operating room asked him what he was feeling. Larsen said, “I don’t know why, but I feel happy. I feel like laughing.”

Doctors continued probing his brain for hours, figuring out what areas — and what level of stimulation — might work weeks later, when Larsen would have his device turned on for good.

In the weeks after surgery, the residual swelling in his brain kept those good feelings going. For the first time in years, Larsen and his mother had hope for normalcy.

“I know that Brett has a lot of normal in him, even though this disease eats him up at times,” said Michele Larsen. “There are moments when he’s free enough of anxiety that he can express that. But it’s only moments. It’s not days. It’s not hours. It’s not enough.”

Turning it on

In January, Larsen had his device activated. Almost immediately, he felt a swell of happiness reminiscent of what he had felt in the OR weeks earlier.

But that feeling would be fleeting — the process for getting him to an optimal level would take months. Every few weeks doctors increased the electrical current.

“Each time I go back it feels better,” Larsen said. “I’m more calm every time they turn it up.”

With time, some of his compulsive behaviors became less pronounced. In May, several weeks after his device was activated, he could put on his shoes with ease. He no longer spun them around in an incessant circle to allay his anxiety.

But other behaviors — such as turning on and shutting off the faucet — continued. Today, things are better, but not completely normal.

Normal, by society’s definition, is not the outcome Larsen should expect, experts say. Patients with an intractable disease who undergo deep brain stimulation should expect to have manageable OCD.

Lately, Larsen feels less trapped by his mind. He is able to make the once interminable trek outside his home within minutes, not hours. He has been to Disneyland with friends twice. He takes long rides along the beach to relax.

In his mind, the future looks bright.

“I feel like I’m getting better every day,” said Larsen, adding that things like going back to school or working now feel within his grasp. “I feel like I’m more able to achieve the things I want to do since I had the surgery.”

Thanks to Da Brayn for bringing this to the attention of the It’s Interesting community.

http://www.cnn.com/2014/06/24/health/brain-stimulation-ocd/?c=&page=0