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Saturday, April 5, 2014

Electrode placement affects subthalamic nucleus stimulation outcomes

Electrode placement affects subthalamic nucleus stimulation outcomes

Published on April 4, 2014 at 5:15 PM · No Comments

By Eleanor McDermid, Senior medwireNews Reporter

Researchers have identified factors associated with motor, cognitive and mood outcomes after deep-brain stimulation (DBS) of the subthalamic nucleus (STN) in a large cohort of patients with Parkinson’s disease (PD).

The findings confirm that stimulation of the STN, rather than surrounding structures, has the greatest success. Among the 262 patients, 26 had bilateral placement of stimulation contacts in the zona incerta, 17 in the posterior-sensorimotor-STN and 61 in the intermediate- associative-STN.

When assessed 1 year after surgery, patients with bilateral stimulation of the posterior-sensorimotor-STN or intermediate-associative-STN had similar motor outcomes, but those with placement in the zona incerta had significantly higher (worse) scores for motor disability, akinesia, rigidity and axial signs. Within the STN, greater motor improvements occurred with more anterior electrode placement.

Electrode placement also influenced cognitive outcomes, report study author Marie-Laure Welter (Université Pierre et Marie Curie-Paris 6, France) and colleagues. In all, 18% of patients experienced a decline in cognitive performance between baseline and 1 year after surgery and, again, more anterior electrode placement was associated with better outcomes.

However, the researchers believe that stimulation per se is not likely to affect cognitive outcomes. The patients with cognitive decline after surgery had no further decline between 1 and 2 years postsurgery, which “suggests that the main factor related to its occurrence is the surgical procedure creating a microlesion.”

Some psychiatric outcomes were also linked to electrode placement, with contacts in the 19 patients who developed transient hypomania tending to be placed deeper than in those without, and being associated with placement in the STN rather than the zona incerta. By contrast, continuing or new depression was associated only with patients’ cognitive performance.

“This confirms the role of the STN in motor and nonmotor processing and its possible importance in nonmotor diseases”, writes the team in Neurology.

Finally, the researchers stress the “dramatic” effect of DBS–STN in their homogeneous cohort selected according to strict criteria, with an overall 64% improvement in motor disability.

“Such improvement is greater than that reported by others using less restrictive inclusion criteria”, they say. “This argues for the strict selection of patients to obtain the best motor outcome with minimum side effects.”

Wednesday, March 26, 2014

Transcranial Magnetic Stimulation Offers Hope for Patients with Intractable Depression


Transcranial Magnetic Stimulation Offers Hope for Patients with Intractable Depression


By: Jennifer Webster
Monday, March 24, 2014
Filed under: Medical Devices | Technology | Treatments & Techniques | Psychiatry

NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy, an FDA-approved, nonpharmacologic method of neuromodulation, lifts depression in a number of people for whom medical management has failed.

Photo: Martha St. John, MD, FAPA, uses the Neurostar TMS Therapy System.

Although the FDA approved the NeuroStar TMS Therapy System in 2008, only about 12,000 patients have received treatment so far, though one in 10 people in the United States takes antidepressant medications.

“This therapy slid under the radar,” says Martha St. John, MD, FAPA, who practices at Progressive Psychiatry TMS Center. “Many psychiatrists, not to mention primary care providers, do not understand TMS’ utility and where it fits into the treatment algorithm.”

Major depression takes a large toll on patients in the United States, accounting for $34 billion in absenteeism and other workplace costs, increasing mortality rates in people with other illnesses, and greater likelihood that people will commit suicide.

Unfortunately, depression remains untreatable in many cases. Only about half of patients respond well to the first antidepressant they try; after that, success rates decline to 25–30 percent with the second medication and even lower with subsequent prescriptions. TMS offers an effective alternative.

“It is exciting to offer a treatment that is so novel and actually works for a population of people suffering from major depression who do not benefit from traditional medical management.”
— Martha St. John, MD, FAPA, psychiatrist practicing at Progressive Psychiatry TMS Center

In a large-scale study by Neuronetics, NeuroStar’s manufacturer, 62 percent of patients with treatment-resistant depression experienced relief from their depression after completing TMS therapy, with 41 percent of those experiencing total remission. These numbers remained stable and even improved over time, with 68 percent of patients enjoying greater freedom from symptoms and 45 percent of those experiencing remission 12 months following completion of therapy.

“When I investigated NeuroStar TMS Therapy, I was very attracted to it as a way to benefit my patients,” Dr. St. John says. “There is a tremendous need to expand our options for treating depression. With efficacy exceeding what we can expect from medication in most cases and minimal side effects, TMS looked extremely promising.”

The Science of TMS

Neuro Star 250

TMS uses electromagnetic induction to depolarize neurons in the dorsolateral prefrontal cortex (DLPFC). An electrical current passed through a coil generates a magnetic field, and a current generated in the opposite direction transforms the magnetic field into an electrical field within the DLPFC. The electrical field causes nearby neurons to release neurotransmitters, such as dopamine, norepinephrine and serotonin.

“One way to put the neural circuits back in balance is chemically with medication,” explains Dr. St. John. “Alternatively, because the brain is basically a large circuit, we can activate the outside 2 to 3 cm of the prefrontal cortex magnetically, then utilize the brain’s natural circuitry to stimulate more distal regions, such as the anterior cingulate cortex and amygdala.”

The process continues during and between sessions, which typically last about 40 minutes and are repeated regularly from four to six weeks, for an average of 30 sessions.

Side effects of TMS are quite rare, but this therapy does have the potential to produce mania in people with bipolar disorder. The only contraindication to TMS therapy is presence of an implanted metallic device within 30 cm of the treatment coil. It is not recommended for patients who have seizure disorders, are pregnant or are very elderly.

The patient experience reflects the simplicity of this noninvasive technology. After a first session to establish dosing, patients come daily for a month to a month and a half, spending just over half an hour sitting comfortably for treatment. They do not need sedation or protective equipment, apart from earplugs, and they are able to drive themselves home after each session. They may experience a headache or scalp discomfort.

All of her patients express gratitude for the opportunity to receive TMS therapy, Dr. St. John says.

“Every patient would do it again or recommend it to someone else,” she says. “We have had an overwhelmingly positive response.”

The high rate of anecdotal satisfaction echoes the experience of other clinicians and their patients, Dr. St. John adds.

“An NIMH [National Institute of Mental Health] study confirmed that about 30 percent of patients with medication-resistant depression achieve remission with TMS, but experientially, it’s higher,” she says. “Psychiatrists believe this is because, while patients were withdrawn from their medications before undergoing TMS for research purposes, the common practice is to use TMS as augmentation to medications, rather than replacement. We commonly obtain much better results than are published.”

Make the Connection

Martha St John 175
Dr. St. John practices at Progressive Psychiatry TMS Center.

The longer depression lasts, the less likely it is to respond to treatment. Dr. St. John encourages referring primary care physicians, counselors and others who have patients struggling with depression to consider early referrals.

“We would like to help patients early in their illness ,” she says. “Patients who have tried one to three antidepressant medications at a reasonable dosage and duration but have not had a good response or have experienced intolerable side effects are good candidates for TMS.”

Patients who come to Dr. St. John’s practice, Progressive Psychiatry TMS Center, will find an experienced staff ready to assist them in obtaining insurance coverage for their treatment. In fact, Texas’ Medicare contractor, Novitas, has covered TMS since December 2013.

“Depression is a pervasive illness, affecting 14 million people in the United States,” Dr. St. John says. “We all know someone or treat someone whose life has been touched by it. Unfortunately, a lot of patients are receiving inadequate treatment. We need to treat depressed patients more aggressively. NeuroStar provides hope even for treatment-resistant patients. When TMS is considered earlier in the treatment algorithm, it allows patients to improve their quality of life much sooner.”

To refer a patient to Progressive Psychiatry TMS Center, visit or call 281-987-5036.

MD News February/March 2014, Houston Edition





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1 comment for “Transcranial Magnetic Stimulation Offers Hope for Patients with Intractable Depression”
  1. Gravatar of Herbert SteinHerbert Stein

    Posted Wednesday, March 26, 2014 at 1:47:23 PM

    To Whom It May Concern:

  2. As a very, very long-term support person and mental health advocate/activist for my spouse I would like to address an important point missing from this and similar articles.

  3. While this treatment option has also been FDA approved as was VNS (Vagus Nerve Stimulation) Therapy what you all seem to omit and not address and what is most important to the patient and/or his/her support persons is the fact that CMS (Centers for Medicare and Medicaid Services) has not approved national coverage. At best TMS is covered by Medicare/Medicaid and private health insurance carriers on a spotty basis. In the case of VNS, although this treatment option was FDA approved in 2005, it was declined by CMS on May 4, 2007.

  4. I should know as I have been battling CMS and the private health insurance carriers to at the very least cover the original study subjects for VNS Therapy and all those who obtained implants on or prior to May 4, 2007. This has been an egregious, immoral and discriminatory oversight on the part of government to allow these patients to be implanted with medical devices and then refuse medical coverage for these seriously ill patients who responded and obtained efficacy from this treatment option. It has been a major struggle on my part to make any advances and one which the various medical associations and physicians should join forces to overcome.

  5. So what good is VNS at a cost of about $58,000 or TMS at a cost of about $10,000 to $15,000 out-of-pocket to the patient if the health insurance companies and Medicare/Medicaid will not pay and the patient cannot afford the therapy?

  6. You folks want a story to write about? I’ll give you a story to write about; available FDA approved treatments denied by CMS and the health insurance industry that patients cannot afford.

  7. Sincerely,

  8. Joyce and Herbert Stein
    1008 Trailmore Lane
    Weston, FL 33326-2816
    (954) 349-8733

Easing Epilepsy With Battery Power

Easing Epilepsy With Battery Power



Kevin Ramsey, an epilepsy sufferer who has a stimulator in his skull, used a wandlike device to download data on his brain activity. Credit Herb Swanson for The New York Times

ALEXANDRIA, N.H. — For most of his life, Kevin Ramsey has lived with epileptic seizures that drugs cannot control.

At least once a month, he would collapse, unconscious and shaking violently, sometimes injuring himself. Nighttime seizures left him exhausted at dawn, his tongue a bloody mess. After episodes at work, he struggled to stay employed. Driving became too risky. At 28, he sold his truck and moved into his mother’s spare bedroom. 

Cases of intractable epilepsy rarely have happy endings, but today Mr. Ramsey is seizure-free. A novel battery-powered device implanted in his skull, its wires threaded into his brain, tracks its electrical activity and quells impending seizures. At night, he holds a sort of wand to his head and downloads brain data from the device to a laptop for his doctors to review.

“I’m still having seizures on the inside, but my stimulator is stopping all of them,” said Mr. Ramsey, 36, whose hands shake because of one of the three anti-seizure drugs he still must take. “I can do things on my own I couldn’t do before. I can go to the store on my own, and get my groceries. Before, I wouldn’t have been able to drive.”


Play Video



An Implant to Prevent Seizures

NeuroPace’s RNS system is an implantable device that prevents seizures in patients plagued by epilepsy.

Just approved by the Food and Drug Administration, the long-awaited device, called the RNS System, aims to reduce seizures and to improve the lives of an estimated 400,000 Americans whose epilepsy cannot be treated with drugs or brain surgery. “This is the first in what I believe is a new generation of therapy for epilepsy,” said Dr. Dileep R. Nair, head of adult epilepsy at the Cleveland Clinic and an investigator in the pivotal trial for NeuroPace’s RNS. “It’s delivering local therapy. It’s not taking tissue out; the brain is left intact. And it’s unlike a drug, which is a shotgun approach.”

Already, Dr. Nair’s center has 70 people on a waiting list for the device. Roughly 110 epilepsy centers with sophisticated diagnostic testing have filed paperwork to be able to offer it, said Dr. Martha J. Morrell, the chief medical officer at NeuroPace, based in Mountain View, Calif. That represents most of the estimated 130 Level 4 centers that treat adults with epilepsy.

Unfortunately, many patients are not referred to these centers by their doctors until they have spent years, even decades, grappling with their condition.

“We want this yesterday,” said Dr. Orrin Devinsky, director of the Comprehensive Epilepsy Center at NYU Langone Medical Center. Next month, pending insurance approval, the center plans to implant the device in its first patient.

An estimated 2.3 million adults nationwide have epilepsy, and in a third of them, seizures are not controlled by drugs. Brain surgery can relieve seizures completely, but many patients aren’t candidates because their seizures start in parts of the brain that can’t be removed, such as those needed for language or memory.

Without treatment options, people with intractable epilepsy often find it difficult to hold jobs or to find spouses. They can suffer repeated injuries from falls and burns; their mortality rate is two to three times higher than that of the general population. “There are people out there who are just desperate for the next treatment,” said Janice Buelow, the vice president of research for the Epilepsy Foundation.

With his neurostimulator, Mr. Ramsey, who is partial to ice fishing and wisecracks, is living on his own in a patched-up trailer heated by an indoor wood stove. Inside is the mounted head of a deer he shot. He drives his purple Ford Ranger to appointments at Dartmouth-Hitchcock Medical Center.

Lately, he’s started to look for part-time work. But he’s cautious. “Because of my epilepsy, a lot of people don’t want to take the risk,” he said.

His treatment has been more successful than most. In a randomized clinical trial of 191 people at 32 sites, patients received stimulators but did not know whether they were activated or not. Those with stimulators activated reported a 38 percent reduction in seizures over three months, compared to a 17 percent decrease among those whose stimulators were not, according to the results published in Neurology. Over two years, 90 subjects with the devices turned on experienced a 50 percent or greater reduction in seizures.

A new implant tries to anticipate seizures before they happen — and stop them; a new test could help cut down on colonoscopy visits; you may think you can spot someone in a lie, but science says different. David Corcoran, Michael Mason and Jeffery DelViscio

Until he received a stimulator in 2008, Andrew Stocksdale, 32, of Mansfield, Ohio, experienced up to 20 seizures a day. By contrast, in the past month, he’s had three. He is now married, holds a full-time job, and has a newborn son.

“My life fell together like a jigsaw puzzle,” Mr. Stocksdale said. “I was afraid to have a son before. I couldn’t do things. I was afraid of falling. I couldn’t hold him.”

Implantation surgery requires two days in the hospital, but extensive evaluation is necessary beforehand, including days of monitoring without anti-seizure drugs.

The device, which requires a battery change every two to three years, works only for people whose seizures start in one or two places in their brain. Electrical stimulation delivered through thin wires placed precisely at those places helps prevent an incipient seizure from spreading.

By contrast, another treatment, a vagus nerve device — which is a stimulator implanted in the chest to prevent seizures — fires “on a preprogrammed basis with no relationship to what’s happening in the brain,” said Dr. Devinsky of the NYU Langone epilepsy center.

Before the RNS is turned on, a patient’s unique seizure patterns must be detected, a process that takes months and multiple clinic visits. Then comes a period of trial and error, when the intensity of stimulation is increased or decreased, or the number of pulses altered, to see if the patient experiences fewer seizures.

“I like to call it a smart device,” said Dr. Christianne Heck, an investigator in the RNS study who is the medical director of the comprehensive epilepsy program at the University of Southern California. “We actually teach the device to detect specific patterns that represent a seizure for each particular patient.”

Soon after Mr. Ramsey’s stimulator was turned on, his major convulsive seizures stopped, said Dr. Barbara C. Jobst, the director of the epilepsy program at Dartmouth-Hitchcock, who was also an investigator in the study. But it took three years of tweaking to stop another kind of seizure that resulted in his simply staring.

Mr. Ramsey’s case was in some ways exceptional, she warned: “It’s not always as clear where the seizures are coming from as it is in him.”


An X-ray shows the neurostimulator implanted in the brain of a patient. Credit NeuroPace

The size of the area where seizures start also affects how well the neurostimulator works, said Dr. David W. Roberts, a neurosurgeon at Dartmouth-Hitchcock. “If a patient’s seizures are confined to the hippocampus, you have a good chance of helping him,” he said, noting that the hippocampus is small.

But if seizures originate over the whole frontal lobe, Dr. Roberts said, the same number of electrical leads are “much less likely to have the same effect.”

Even for patients who are good candidates, access to the new device may be difficult if patients aren’t referred to Level 4 epilepsy centers. Such centers tend to be near universities or larger cities. New York City has eight, while no Level 4 centers exist in Montana, Arkansas or the Dakotas.

Dr. David M. Labiner, the president of the National Association of Epilepsy Centers, said the “lag time” between diagnosis and referral to a comprehensive center “is still up to 20 years.”

Another hurdle is cost. The RNS, with the equipment required to download data, is up to $40,000. That figure doesn’t include $10,000 to $20,000 for the surgery, or diagnostic testing. Thus far, insurers have paid most of the expenses for five or so cases since F.D.A. approval, including one covered by Medicare.

In the long run, seizure reduction is cost-effective, some experts argued.

“Even if seizures are only cut in half, insurers’ costs are cut in half,” said Dr. Labiner, who also heads the epilepsy program at the University of Arizona.

RNS may reduce seizure frequency, but it won’t cure memory loss or repair a difficult marriage. “Psychosocial problems aren’t necessarily better if your seizures are well controlled,” said Dr. Gregory L. Barkley, co-founder of the epilepsy program at Henry Ford Hospital in Detroit. 

Mr. Ramsey still has cognitive issues. “I forget people’s names all the time,” he said. At a restaurant in January, he kept forgetting he had decided to order the seafood pie moments before.

As much as his neurostimulator has changed his life, he’s hoping for another sea change: “Finding a really nice girl,” he said. “I would like to have a baby so I can raise a family.”

A version of this article appears in print on March 25, 2014, on page D1 of the New York edition with the headline: Easing Epilepsy With Battery Power.

Friday, March 21, 2014

Advanced Technology Helps Reduce Seizures For WJ Resident


Advanced Technology Helps Reduce Seizures For WJ Resident

March 13, 2014 | Vol 14 | Issue 2

Erik Wright is living a full life thanks to a new treatment he received for his epilepsy.

Living with seizures is a reality for many people. It is often a guessing game to find the right medication or treatment, and is different for each individual. Even a good medication is usually accompanied by various side effects. Thirty-seven year old West Jordan resident Erik Wright has been searching for the right treatment since he was diagnosed with epilepsy when he was five years old. Finally, he tried something new.

"Erik's neurologist suggested Vagus Nerve Stimulation Therapy, a small pacemaker-like device for the brain," said Danielle Furman from Cyberonics, the company that developed VNS. "When he feels a seizure coming on, he swipes the magnet over his chest and is able to make the aura disappear, and potentially avoid a full seizure almost immediately."

Erik used to suffer several seizures a week, even when he was taking six pills a day. Now with VNS, his seizures have been reduced dramatically and he is taking less medication.

"I'm on three pills a night now, where I was taking six a day before," Wright said. "I think the last seizure I had was back in October."

The VNS device is implanted in the chest and is connected to a small wire that attaches to the vagus nerve in the head. It sends small regularly scheduled impulses to the brain, and can also be activated by swiping a magnet across the device on the chest.

"It goes off every five to 10 minutes. If I feel a seizure coming on, I just take the magnet and swipe it across," Wright said. "In other cases, say someone is having a seizure, a parent, family member or even a friend could use the magnet on the person having a seizure and help it end sooner." Wright keeps his magnet with him all the time. Doctors can adjust the impulse frequency and intensity to suit each individual.

This kind of seizure control has meant a new way of life for Erik. He feels more confident, is more outgoing and travels much more.

"I feel better. I even took two trips to Brazil by myself. I've got a sweetheart back there that I'm trying to get here now," Wright said. He has been asked to speak at seminars about VNS treatment and has been a local resource for patients considering the procedure.

"I think it's really changed my life," Wright said.

Thursday, March 20, 2014

Eavesdropping Deep within the Brain


Eavesdropping Deep within the Brain

Long-term recordings of neural activity may help researchers understand the roots of depression and OCD

Mar 20, 2014 |By Helen Shen and Nature magazine

neuro interface video - screen grab
A neural interface provides a way to communicate with the human central and nervous systems.
Credit: Lawrence Livermore National Laboratory/YouTube

For Frank Donobedian, sitting still is a challenge. But on this day in early January, he has been asked to do just that for three minutes. Perched on a chair in a laboratory at Stanford University in California, he presses his hands to his sides, plants his feet on the floor and tries with limited success to lock down the trembling in his limbs — a symptom of his Parkinson's disease. Only after the full 180 seconds does he relax.

Other requests follow: stand still, lie still on the floor, walk across the room. Each poses a similar struggle, and all are watched closely by Helen Bronte-Stewart, the neuroscientist who runs the lab.

“You're making history,” she reassures her patient.

“Everybody keeps saying that,” replies the 73-year-old Donobedian, a retired schoolteacher, with a laugh. “But I'm not doing anything.”

“Well, your brain is,” says Bronte-Stewart.

Like thousands of people with Parkinson's before him, Donobedian is being treated with deep brain stimulation (DBS), in which an implant quiets his tremors by sending pulses of electricity into motor areas of his brain. Last October, a team of surgeons at Stanford threaded the device's two thin wires, each with four electrode contacts, through his cortex into a deep-seated brain region known as the subthalamic nucleus (STN).

But Donobedian's particular device is something new. Released to researchers in August 2013 by Medtronic, a health-technology firm in Minneapolis, Minnesota, it is among the first of an advanced generation of neurostimulators that not only send electricity into the brain, but can also read out neural signals generated by it. On this day, Bronte-Stewart and her team have temporarily turned off the stimulating current and are using some of the device's eight electrical contacts to record abnormal neural patterns that might correlate with the tremors, slowness of movement and freezing that are hallmarks of Parkinson's disease.

Until now, such data have been accessible only when a patient's brain is exposed briefly during surgery. But being able to make long-term neural recordings from human patients may become increasingly important — especially because researchers are experimenting with using DBS as a treatment for many other neurological conditions, including depression, obsessive–compulsive disorder and Tourette's syndrome. The networks involved in such disorders are even less well understood than those involved in Parkinson's disease, says Helen Mayberg, a neurologist at Emory University in Atlanta, Georgia. Devices such as Donobedian's could change that, allowing scientists to start to understand just how unhealthy neural networks misfire in different diseases, and what DBS actually does to the brain. “Every disease will be different and one size won't fit all,” Mayberg says. “The new technology is going to enable progress exponentially.”

Eventually, adds Bronte-Stewart, engineers could use the new-found knowledge about brain networks to build even more-advanced brain implants — devices that could interpret the neural signals they record, monitor their own effectiveness and generate personalized treatments.

“This is such an exciting time,” she says. “This is the first time we're really getting a window into the brain.”

'Black box' beginnings
The roots of DBS reach back to the 1960s, when Parkinson's disease was commonly treated with surgery to remove or destroy certain brain regions. To pinpoint which areas to target in each patient, some neurosurgeons began to experiment with electrical stimulation. They discovered that the delivery of rapid pulses to the basal ganglia — a cluster of structures including the STN — could markedly reduce the patient's tremors. By the late 1980s, long-term brain stimulation started to emerge as an alternative treatment to surgery. DBS has since been approved for the treatment of Parkinson's and other movement disorders by both the US Food and Drug Administration (FDA) and European regulators, and has been used in more than 100,000 people.

The biological mechanism underlying DBS remains mysterious, and is a subject of controversy. “We've been guessing a lot over the last decade or two,” says Michael Okun, a neuroscientist at the University of Florida in Gainesville. “It would be premature for anyone to claim they know exactly how the therapy works.”

There are some clues, however. For example, DBS is not thought to mimic any natural signals in the brain. The high-frequency pulses — delivered at 130–180 times per second for Parkinson's disease — exceed the 1–100-hertz frequency range of most natural neural communications. Furthermore, with each 60–90-microsecond burst, DBS typically delivers several orders of magnitude more current than any neuron or groups of neurons can produce.

And it does not seem to produce permanent changes in the brain, at least not when applied to Parkinson's disease, currently one of the most common targets of the technology. Turning on the current can produce immediate relief from symptoms such as tremor and rigidity. But in many people, symptoms return seconds or minutes after the device is turned off, or the battery runs out — which happens every 3–5 years. Nor does the therapy halt the progressive neurodegeneration associated with the disease; in the long run, patients will typically succumb to symptoms that are not well treated by DBS, such as cognitive deterioration.

Credit: Nature magazine

From the evidence gleaned so far, researchers suspect that DBS does more than affect neural tissue at the site of the electrodes: it somehow disrupts pathological signals that reverberate through multiple brain regions, corrupting their communications (see 'Circuit training').

That theory meshes with the emerging view that Parkinson's disease, as well as depression and many other neuropsychiatric conditions are best understood as network dysfunctions. “That's a really important realization that has caught on in the last five years,” says Cameron McIntyre, a biomedical engineer at Case Western Reserve University in Cleveland, Ohio. Indeed, it has helped to launch two major neuroscience efforts in the past year: the US Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and the European Union's Human Brain Project.

The primary target of DBS for Parkinson's disease, for example — the STN — sits in the middle of a highly interconnected brain network that helps an individual to control his or her motions. There is some evidence that as Parkinson's destroys neurons in the basal ganglia, the activity of groups of cells in the STN and across this sensorimotor network becomes abnormally synchronized, locking at certain frequencies. DBS seems to release them from these activity patterns, as do some of the drugs that relieve Parkinson's symptoms.

Recordings from the new generation of neurostimulators are poised to elucidate these mechanisms, not just for Parkinson's but also — as DBS applications broaden — for psychiatric conditions. The data could help to resolve concerns about the wisdom of expanding the treatment's usage. Although the sensorimotor network involved in Parkinson's disease has been mapped in great detail, says Joseph Fins, a medical ethicist at Weill Cornell Medical College in New York City, much less guidance is available on how best to apply the technology to other disorders. “There has got to be a biological rationale for what you're intending to do,” he says.

But others argue that controlled testing of DBS in humans need not wait for complete or near-complete understanding of the relevant networks. “As a clinician, that's not really the important question,” says Benjamin Greenberg, a psychiatrist at Brown University in Providence, Rhode Island. “The real questions are: do these treatments help people? Are they safe?”

Okun adds that, unlike the field of movement disorders, the mechanistic study of neuropsychiatric disorders has been slowed by a lack of realistic animal models. “If we're going to move forward with some of these human diseases, we are going to have to use humans — in a very careful way, of course,” he says.

Zooming in
Mayberg has been doing just that for more than a decade. In 2005 she published one of the first studies on the use of DBS to alleviate severe, treatment-resistant depression. Since then, she has mainly focused her experiments on a structure known as the subgenual cingulate, in which elevated metabolism has been shown to correlate with the severity of a patient's depression. She estimates that the use of DBS in this region and elsewhere has successfully eased symptoms in 40–60% of the roughly 150 cases of depression reported on so far. But in recent years, her group has begun to do better by using brain imaging to map the dense web of nerve fibres zigzagging through and around the subgenual cingulate, which connects to regions involved in learning, motivation, appetite and sleep. Combining this information with the effects seen in patients, Mayberg is zeroing in on millimeter-scale differences in electrode placement that can make the difference between success or failure.

Potentially, she says, new implants such as the device being tested by Bronte-Stewart could help her team to do even better, allowing researchers to monitor patients' condition in real time and fine-tune the stimulation pulses to maximize benefit. “There may be an optimal tuning frequency for a given person, and it may not be the same for everyone,” she says.

Creating personalized DBS treatments is a top priority in this field. Just before Donobedian's meeting with Bronte-Stewart, his neurologist, Camilla Kilbane of Stanford University, spends half an hour tuning the device's stimulation settings to address his symptoms.

Using a short-range radio device, she programs a pulse generator implanted in Donobedian's upper chest. The generator — about half the size of a deck of cards — sends electrical pulses through insulated wires that run under the skin of his neck and scalp, and into his brain. Kilbane has already determined during a previous visit the subset of electrode contacts she wants to tweak, and Donobedian has stopped taking his supplementary Parkinson's drugs overnight so that Kilbane can cleanly isolate the effects of neurostimulation.

As she drops the voltage and the implant can no longer overcome Donobedian's tremors, his hands and feet begin to quiver again. Within seconds, the tremors grow and spread, until his arms clap against his sides and his shoes tap the linoleum floor. Kilbane clicks the voltage up again, and Donobedian's limbs calm down — but then his arms begin to tingle, a common side effect of DBS. At intermediate voltages, his right leg stops shaking, but the other continues to tremble.

“It's stubborn, that left foot!” remarks Kilbane. She spends another 10 minutes inching the voltage up and down, gradually homing in on an optimal setting. Even after this, Donobedian may need to return in the coming months for further fine-tuning.

“What we have right now for DBS works, but it's very much the first generation,” says Bronte-Stewart. She and others are using the new recording-capable DBS implants as a stepping stone towards 'closed-loop' neurostimulators — devices that can continuously track an individual's brain activity and automatically optimize settings as needed in real-time. As a first step, the Stanford group is beginning to mine the electrical recordings downloaded wirelessly from the implants in Donobedian and other patients to find patterns that correlate with different Parkinsonian symptoms. They are also looking to see how these patterns might change in the context of different actions, such as sitting, standing and walking — data that could not be obtained with bulky hospital machines. Indeed, Bronte-Stewart says, there may not be just one set of 'optimal' stimulation parameters. “We may find out there are different frequency ranges that are better for different functions,” she says.

Smarter stimulation
As scientists collect more data, some manufacturers are already starting to make strides in closed-loop technology. Last November, the FDA approved the first closed-loop, implantable neurostimulator for intractable epilepsy, another disorder attributable to network dysfunction. The device, made by NeuroPace in Mountain View, California, monitors neural networks for the first sign of abnormal activity — which in some patients originates again and again at one or a few 'epileptic foci' — then responds with a pulse of electrical current to prevent a seizure. “We use stimulation to disrupt that abnormal activity so that it doesn't get picked up by the adjacent neurons,” explains Frank Fischer, the company's chief executive.

But Fischer concedes that, whatever the device might do for epilepsy treatment, the technology is not immediately applicable to other conditions. Epilepsy is a comparatively simple disorder, generally consisting of discrete episodes of abnormal brain activity. By contrast, Parkinson's disease involves a mishmash of symptoms that rise, fall and morph over time. Researchers are still searching for the relevant neural signatures in Parkinson's and other diseases, and developing the computational tools required to keep up with changing symptoms.

The first laboratory demonstration of a closed-loop DBS system for Parkinson's disease was reported last year by experimental neurologist Peter Brown at the University of Oxford, UK, for a group of eight patients. Brown plugged the patients' DBS implants into an external machine, which triggered stimulation of the STN only when certain abnormal brain rhythms were detected. This selective stimulation improved the symptoms by almost 30% compared with standard DBS treatments, which stimulate the brain at regular intervals.

“It's far short of being introduced into patients,” says Brown of the bulky experimental system, but the demonstration does provide an important proof that the closed-loop concept could work for Parkinson's disease.

In an effort to accelerate the move towards closed-loop technology, the US Defense Advanced Research Projects Agency (DARPA) last October announced a 5-year, $70-million program to support the development of novel brain stimulators. As part of the BRAIN Initiative, the project aims to foster brain implants to treat conditions such as post-traumatic stress disorder, anxiety and traumatic brain injury. The agency is looking for implantable devices that can monitor and manipulate neural activity not just at one or a few sites at a time, but across entire functional networks of neurons. Accomplishing this goal will require the development of new types of miniaturized sensor, as well as detailed network models of brain function to interpret data streaming in from multiple brain areas, says DARPA program manager Justin Sanchez.

Some of those models may eventually grow out of data from researchers such as Kendall Lee, a neurosurgeon at the Mayo Clinic in Rochester, Minnesota. At last year's Society for Neuroscience meeting, he presented a prototype DBS system called Harmoni that can deliver current to one area of the brain while recording electrical and neurochemical responses elsewhere (see Nature; 2013). Because the brain uses both electrical and chemical signals to communicate, explains Kevin Bennet, the lead engineer on the project, monitoring each type of data could provide more complete information about what is going on. The group intends to test Harmoni first in patients with movement disorders. But, ultimately, the scientists hope to extend combined chemical and electrical monitoring to psychiatric disorders. “Those will be the most difficult to treat,” says Bennet. “The symptoms are harder to detect and quantify.”

Bronte-Stewart projects that testing might begin in about five years for the first implantable, closed-loop DBS devices for Parkinson's disease, with psychiatric applications following close behind. It is not clear whether Donobedian and other current research volunteers could be easily upgraded to those systems; much depends on the precise design of the devices. But even if he does not benefit directly from the data he is generating, Donobedian is glad to participate.

“Somebody had to give to me, to get this far,” he says. “If there's a chance for me to give something back without too much effort, I'd like to help.”

This article is reproduced with permission from the magazine Nature. The article was first published on March 19, 2014.

Friday, March 14, 2014

NIH announces recruitment for clinical trial to test new tinnitus treatment device


National Institute on Deafness and Other Communication Disorders (NIDCD)


Robin Latham


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Embargoed for Release: Thursday, March 6, 2014, 12 p.m. EST

NIH announces recruitment for clinical trial to test new tinnitus treatment device

Multi-center trial offers hope for millions of Americans with severe tinnitus

Researchers supported by the National Institutes of Health are launching a clinical trial to test a device that uses nervous system stimuli to rewire parts of the brain, in hopes of significantly reducing or removing tinnitus, a persistent buzzing or ringing sound in the ears in the absence of any real sound.

An illustration showing new tinnitus treatment

This illustration shows how the new device to treat tinnitus will operate.

The small clinical trial, which is recruiting volunteers, is being conducted at four centers through a cooperative agreement with MicroTransponder, Inc., a medical device company based in Dallas.

Roughly 10 percent of the adult population of the United States has experienced tinnitus lasting at least five minutes in the past year, and approximately 10 million of them have been bothered enough by the condition to seek a doctor. Although tinnitus may be only an annoyance for some, for others the relentless ringing causes fatigue, depression, anxiety, and problems with memory and concentration. Available treatments help some people cope, but current therapies lack the potential to significantly reduce the bothersome symptoms of tinnitus.

The trial, supported by the National Institute on Deafness and Other Communication Disorders (NIDCD), a part of NIH, may mark the beginning of a change in how tinnitus is treated.

“Tinnitus affects nearly 24 million adult Americans,” said James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. “It is also the number one service-connected disability for returning veterans from Iraq and Afghanistan. The kind of nervous system stimuli used in this study has already been shown to safely and effectively help people with epilepsy or depression. This therapy could offer a profoundly better way to treat tinnitus.”

Most cases of chronic tinnitus are preceded by a loss of hearing as the result of damage to the inner ear from aging, injury, or long-term exposure to loud noise. When sensory cells in the inner ear are damaged, the resulting hearing loss changes some of the signals sent from the ear to neurons in the auditory cortex of the brain. Scientists still haven’t agreed upon what happens to create the illusion of sound when there is none, but the therapy being tested in this new clinical trial attempts to ameliorate the phantom sound of tinnitus by going to its source – the brain.

The auditory pathway is organized by what scientists call the tonotopic map, a structural arrangement in which different tone frequencies are transmitted separately along specific parts of the pathway. Hearing loss is the result of a loss in the ability of the auditory system to process certain frequencies. Earlier studies showed that the loss of the ability to hear these frequencies matched patterns of distortion in the neurons of the auditory cortex’s tonotopic map.

This research suggests that tinnitus might be the result of the brain trying to regain the ability to hear those lost frequencies by turning up the signals of neurons in neighboring frequencies. Because there are too many neurons processing the same frequencies, they fire more strongly, more frequently and in concert with each other, even when the environment is quiet. It is these changing brain patterns that researchers believe could produce the perception of whooshing, ringing, or buzzing in the ear that characterizes tinnitus.

The new study uses a technique known as vagus nerve stimulation (VNS) that takes advantage of the brain’s ability to reconfigure itself (neuroplasticity). During the therapy, patients wear headphones and hear a series of single frequency tones, paired with stimulation to the vagus nerve, a large nerve that runs from the head and neck to the abdomen. When stimulated, the vagus nerve releases acetylcholine, norepinephrine, and other chemicals that encourage neuroplasticity.

In an earlier NIDCD-funded study using a rat model, the technique was shown to reorganize neurons to respond to their original frequencies, subdue their activity, and reduce their synchronous firing, suggesting that the ringing sensation had stopped. The scientists subsequently tested a prototype device in a small group of human volunteers in Europe and observed encouraging results.

For this new study, two groups of adults who have had moderate-to-severe tinnitus for at least one year will participate in daily 2.5 hour sessions of VNS and audio tone therapy over six weeks. One group will get the VNS and tone test treatment immediately; the other will get a combination of VNS and tones that is not expected to have a therapeutic benefit. After six weeks, both groups will receive active test treatment.

Outcomes will be measured throughout the year-long trial using the Tinnitus Functional Index and the Tinnitus Handicap Questionnaire, two questionnaires that allow patients to report on the extent of their tinnitus. They will also be tested periodically to determine changes in minimum masking levels for the tinnitus – the decibel level of sound required to eliminate awareness of the tinnitus.

“This trial has the potential to open up a whole new world of tinnitus management,” says Gordon Hughes, M.D., director of clinical trials at the NIDCD. “Currently, we usually offer patients a hearing aid if they have hearing loss or a masking device if they don’t. None of these treatments cures tinnitus. But this new treatment offers the possibility of reducing or eliminating the bothersome perception of tinnitus in some patients.”

The clinical trial sites are at the University of Texas at Dallas; University at Buffalo (SUNY), Buffalo; and the University of Iowa, Iowa City. An additional site will be added later in the year. More information about the trial and enrollment is available on the study’s website, External Web Site Policy, or at (NCT01962558).

“The support of the NIDCD has been essential to bringing this novel tinnitus therapy into the clinic,” said MicroTransponder, Inc. CEO Frank McEachern. “The translation of scientific discovery into medical therapies is a long and difficult path. The NIH recognized the importance of our tinnitus research early on, which enabled us to secure additional private funding for the extensive development effort required to build a device for clinical trials.”

The research is supported by NIDCD grant U44DC010084. Additional support for the University of Texas at Dallas research is provided by the Texas Biomedical Device Center.

For more information about tinnitus, see our fact sheet at

NIDCD supports and conducts research and research training on the normal and disordered processes of hearing, balance, taste, smell, voice, speech, and language and provides health information, based upon scientific discovery, to the public. For more information about NIDCD programs, see the website at

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Effect of noninvasive vagus nerve stimulation on acute migraine: An open-label pilot study.

Cephalalgia. 2014 Mar 7. [Epub ahead of print]

Effect of noninvasive vagus nerve stimulation on acute migraine: An open-label pilot study.

Goadsby P1, Grosberg B, Mauskop A, Cady R, Simmons K.

Author information

We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine.


Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain.


Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching ( N  = 1), raspy voice ( N  = 1) and redness at the device site ( N  = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%).


nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.


Migraine, acute treatment, neuromodulation, vagus nerve

[PubMed - as supplied by publisher]