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Tuesday, May 27, 2014

Rice researcher rebooting 'deep brain stimulation'

Rice researcher rebooting 'deep brain stimulation'

Rice researcher rebooting 'deep brain stimulation'Enlarge

Caleb Kemere. Credit: Jeff Fitlow/Rice University

Deep brain stimulators, devices that zap Parkinson's disease tremors by sending electrical current deep into nerve centers near the brain stem, may sound like they are cutting-edge, but Rice University's Caleb Kemere wants to give them a high-tech overhaul.

Kemere, who's equal parts electrical engineer and neuroscientist, specializes in building electronic devices that interact with the brain. One longtime area of interest is the basal ganglia, the part of the brain that helps govern movement; it's also the nerve center targeted by "deep brain stimulation" (DBS) technology, a neuroelectronic device that's sometimes used to treat patients in the late stages of Parkinson's.

Thanks to a new five-year grant from the National Science Foundation (NSF), Kemere is about to embark on a program to reboot DBS technology with the latest embedded processors and research analytics. The research is funded by an NSF CAREER Award. The NSF gives only about 400 CAREER Awards each year across all disciplines. The program is designed to support the research and career development for young scholars that the agency expects to become leaders in their field. Each award includes about $400,000 in research funding.

"Deep brain stimulation has proven to be remarkably effective in treating Parkinson's, and it may well turn out to be revolutionary for treating severe depression and other neurological and psychiatric disorders," said Kemere, assistant professor of electrical and computer engineering and director of Rice's Realtime Neural Engineering Laboratory.

DBS systems, which are sometimes called "brain pacemakers," deliver a small, continuous current to the basal ganglia of late-stage Parkinson's patients. The technology can produce dramatic results and it allows some Parkinson's patients to walk, speak, write and perform other motor movements that are exceedingly challenging when the device is switched off.

"Today's DBS technology is basically the same as that used in heart pacemakers," Kemere said. "The electrodes are just implanted inside the brain rather than in the heart. I've found that when electrical engineers like myself first hear about DBS, they generally have the same two thoughts: 'Wow, that's a really cool use of electronics,' and 'The brain doesn't pulse like a heart; maybe we can improve this by matching the stimulation to the dynamic nature of the brain!'

"It's that second idea that we're focused on here," said Kemere, who is also an adjunct assistant professor of neurology at Baylor College of Medicine. "We want to develop deep brain stimulation technology that operates on the order of milliseconds, actively detecting what's going on in the brain at any moment and then modulating the stimulation to optimize results. In electrical engineering terms, we call this 'closing the feedback loop.'"

Kemere said today's DBS systems are manually adjusted by neurologists when a patient comes in for an office visit every few weeks or months. In his next-generation DBS, these types of adjustments would be made automatically, many times each second.

"There are several reasons we want to do this," Kemere said. "Though DBS is remarkably effective today, it provides only minimal therapeutic benefit for perhaps a third of Parkinson's patients. It's possible that dynamic DBS could substantially increase effectiveness for these users.

"Also, current DBS technology has side effects, and we'd like to reduce those," Kemere said. "For example, people with Parkinson's have a spectrum of symptoms, including tremors, trouble initiating muscle movement, muscle rigidity and slowness of movement. Sometimes, DBS can relieve one of those symptoms but make another one worse."

Rebooting DBS technology won't be simple. For starters, the real-time computer processing required for dynamic DBS will require power, and power always comes at a premium in implanted medical devices. For example, the battery packs in current DBS systems last for about 10 years, and getting the same kind of battery life from a dynamic system will require a great deal of upfront work to develop low-power embedded microprocessors.

Another research track will involve creating algorithms to properly interpret the incoming neural signals from the brain. Kemere's research group will rely heavily on experiments with rats to create, test and refine systems that can correctly interpret incoming neural signals and respond accordingly.

"We think we can optimize DBS stimulation and maximize its therapeutic benefit if we can better understand how information flows in the cortical-basal ganglia circuits in healthy brains, how those flows are disrupted by Parkinson's disease and how DBS can alter those flows," Kemere said.

Explore further: Deep brain stimulation for obsessive-compulsive disorder releases dopamine in the brain

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Batteries in Implant Devices Can Be Recharged From Outside of the Body

Batteries in Implant Devices Can Be Recharged From Outside of the Body

Added by Sarah Takushi on May 27, 2014.
Saved under Health, Research, Sarah Takushi, Science, Study, Technology
Tags: batteries, top

batteries, battery, pacemaker, mid-field wireless transfer, mid-field, waves, electroceutical, electroceuticals

Stanford University electrical engineers have invented a way to wirelessly recharge the batteries of medically implanted devices from outside the body. Such an invention removes a major impediment towards the use of medical implant devices, and has the potential to open up the field of “electroceuticals,” which would treat illness using electronic devices rather than drug-based therapies. Even current medical implant devices such as pacemakers and nerve stimulator devices could stand to be re-invented as the out-of-body recharging technology would allow bulky batteries to be miniaturized.

Medical implants that run off of electricity are becoming increasingly commonplace within modern medicine. Each year in the United States over 100,000 pacemakers are implanted as a treatment for cardiac arrhythmia. In addition to that, neurological conditions such as epilepsy may be treated with implants such as a vagus nerve stimulatory device (VNS device) which can be used to prevent seizures.

Currently, limited battery life remains a major impediment to the development of more advanced and widely applicable medical implant devices. In the case of pacemakers, when the battery runs out, a patient must go in for surgery to have the device replaced. Although such surgeries are routine and are considered minor operations, as with any invasive treatment, there are always associated risks such as infection, damage to internal organs, and/or the need for additional surgeries.

However, a team of engineers headed by Stanford University assistant professor Ada Poon has developed a way by which medical implant devices can have their batteries recharged from outside of a patient’s body. The new technology exploits the ways in which waves travel differently through different materials.

Modern technology generally uses two different kinds of electromagnetic waves. Those in the far-field range, such as radio waves, are used in communications technology. Though these waves can travel great distances, when they encounter biological material they either bounce off or are absorbed as heat. By contrast, near-field waves do not travel far, but are capable of wirelessly transferring power over those short distances. Poon and her team were able to generate an intermediate form of wave—called mid-field waves—designed specifically to predictably propagate within the mammalian body for power transfer. Consequently, the new recharging method is called “mid-field wireless transfer.”

Mid-field wireless transfer has allowed the large batteries of pacemakers and other devices to be miniaturized down to about the size of a grain of rice. After the medical implant is put into the patient, re-charging the battery is as simple as swiping a credit-card-sized power source above the device.

With the limiting factor of bulky batteries and inconvenience removed, Poon speculates that a new era of electronic-based pharmaceutical devices—electroceuticals—may be at hand. Potentially tiny devices to monitor vital functions, drug delivery systems, and neural stimulator devices could all be made to treat pain and alleviate illness. An advantage of electroceutical devices over traditional drug therapy approaches is the specificity with which such treatments could be employed. While drugs create global effects in the body, may times by way of nasty side effects, electroceuticals could be implanted at specific locations to stimulate exact regions at specified times and frequencies depending upon the needs of the patient.

So far, the wireless recharging system has successfully recharged implant devices in a pig and in a rabbit. Poon and her team are currently preparing to test in humans. If successful, it will still take several more years for the new out-of-body battery recharging technology to be incorporated into commercial medical devices.

By Sarah Takushi


Comprehensive Epilepsy Center

Encyclopedia of Surgery


Palo Alto Medical Foundation

R&D News

Science Daily

Vagus nerve stimulation...25 years later! What do we know about the effects on cognition?

Neurosci Biobehav Rev. 2014 May 21. pii: S0149-7634(14)00122-5. doi: 10.1016/j.neubiorev.2014.05.005. [Epub ahead of print]

Vagus nerve stimulation...25 years later! What do we know about the effects on cognition?

Vonck K1, Raedt R2, Naulaerts J3, De Vogelaere F4, Thiery E5, Van Roost D6, Aldenkamp B7, Miatton M8, Boon P9.

Author information
  • 1Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 2Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 3Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 4Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 5Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 6Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 7Epilepsy Centre Kempenhaeghe, Postbus 61, 5590 AB Heeze, The Netherlands; Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Electronic address:
  • 8Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address:
  • 9Laboratory for Clinical and Experimental Neurophysiology, Neurobiology and Neuropsychology, Department of Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Epilepsy Centre Kempenhaeghe, Postbus 61, 5590 AB Heeze, The Netherlands. Electronic address:

VNS therapy was delivered to patients for the first time in 1988. After 25 years, insight in the antiepileptic and antidepressant mechanism of action of VNS has grown steadily. The effects on cognition and especially memory, remain controversial. This review provides an elaborate overview of studies addressing cognition and describes potential underlying mechanisms for the reported effects. Short term VNS has an effect on verbal memory recognition when adminstered at the correct timing and dosage. Chronic VNS resulted into a positive effect on the cognitive status in an Alzheimer population. Positive effect of chronic VNS in epilepsy or depression patients on global cognitive functioning are less convincing. Neither do the results reveal a negative effect which has major implications for chronic treatment of neurology patients. A cascade of neurochemical processes put in motion by changes in NE concentrations in reaction to stimulation of the vagal nerve may underly the VNS-induced effects on cognition and memory. In Alzheimer pathology, NE may act as an anti-inflammatory agent on brainstem nuclei.

Copyright © 2014. Published by Elsevier Ltd.


Alzheimer's Disease, Quality of life, Vagus nerve stimulation, cognitive functioning, depression, epilepsy, locus coeruleus, memory, norepinephrine

[PubMed - as supplied by publisher]
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Sunday, May 25, 2014

Can the Nervous System Be Hacked?



Magazine |​NYT Now

Can the Nervous System Be Hacked?



Mirela Mustacevic, who suffers from rheumatoid arthritis, had a nerve stimulator implanted as part of a medical trial. Her symptoms have lessened significantly. Credit Sarah Wong for The New York Times


One morning in May 1998, Kevin Tracey converted a room in his lab at the Feinstein Institute for Medical Research in Manhasset, N.Y., into a makeshift operating theater and then prepped his patient — a rat — for surgery. A neurosurgeon, and also Feinstein Institute’s president, Tracey had spent more than a decade searching for a link between nerves and the immune system. His work led him to hypothesize that stimulating the vagus nerve with electricity would alleviate harmful inflammation. “The vagus nerve is behind the artery where you feel your pulse,” he told me recently, pressing his right index finger to his neck.

The vagus nerve and its branches conduct nerve impulses — called action potentials — to every major organ. But communication between nerves and the immune system was considered impossible, according to the scientific consensus in 1998. Textbooks from the era taught, he said, “that the immune system was just cells floating around. Nerves don’t float anywhere. Nerves are fixed in tissues.” It would have been “inconceivable,” he added, to propose that nerves were directly interacting with immune cells.


‘There was nothing in the scientific thinking that said electricity would do anything. It was anathema to logic. Nobody thought it would work.’

Nonetheless, Tracey was certain that an interface existed, and that his rat would prove it. After anesthetizing the animal, Tracey cut an incision in its neck, using a surgical microscope to find his way around his patient’s anatomy. With a hand-held nerve stimulator, he delivered several one-second electrical pulses to the rat’s exposed vagus nerve. He stitched the cut closed and gave the rat a bacterial toxin known to promote the production of tumor necrosis factor, or T.N.F., a protein that triggers inflammation in animals, including humans.

“We let it sleep for an hour, then took blood tests,” he said. The bacterial toxin should have triggered rampant inflammation, but instead the production of tumor necrosis factor was blocked by 75 percent. “For me, it was a life-changing moment,” Tracey said. What he had demonstrated was that the nervous system was like a computer terminal through which you could deliver commands to stop a problem, like acute inflammation, before it starts, or repair a body after it gets sick. “All the information is coming and going as electrical signals,” Tracey said. For months, he’d been arguing with his staff, whose members considered this rat project of his harebrained. “Half of them were in the hallway betting against me,” Tracey said.

Inflammatory afflictions like rheumatoid arthritis and Crohn’s disease are currently treated with drugs — painkillers, steroids and what are known as biologics, or genetically engineered proteins. But such medicines, Tracey pointed out, are often expensive, hard to administer, variable in their efficacy and sometimes accompanied by lethal side effects. His work seemed to indicate that electricity delivered to the vagus nerve in just the right intensity and at precise intervals could reproduce a drug’s therapeutic — in this case, anti-inflammatory — reaction. His subsequent research would also show that it could do so more effectively and with minimal health risks.

Tracey’s efforts have helped establish what is now the growing field of bioelectronics. He has grand hopes for it. “I think this is the industry that will replace the drug industry,” he told me. Today researchers are creating implants that can communicate directly with the nervous system in order to try to fight everything from cancer to the common cold. “Our idea would be manipulating neural input to delay the progression of cancer,” says Paul Frenette, a stem-cell researcher at the Albert Einstein College of Medicine in the Bronx who discovered a link between the nervous system and prostate tumors.

“The list of T.N.F. diseases is long,” Tracey said. “So when we created SetPoint” — the start-up he founded in 2007 with a physician and researcher at Massachusetts General Hospital in Boston — “we had to figure out what we were going to treat.” They wanted to start with an illness that could be mitigated by blocking tumor necrosis factor and for which new therapies were desperately needed. Rheumatoid arthritis satisfied both criteria. It afflicts about 1 percent of the global population, causing chronic inflammation that erodes joints and eventually makes movement excruciating. And there is no cure for it.

In September 2011, SetPoint Medical began the world’s first clinical trial to treat rheumatoid-arthritis patients with an implantable nerve stimulator based on Tracey’s discoveries. According to Ralph Zitnik, SetPoint’s chief medical officer, of the 18 patients currently enrolled in the ongoing trial, two-thirds have improved. And some of them were feeling little or no pain just weeks after receiving the implant; the swelling in their joints has disappeared. “We took Kevin’s concept that he worked on for 10 years and made it a reality for people in a real clinical trial,” he says.

Conceptually, bioelectronics is straightforward: Get the nervous system to tell the body to heal itself. But of course it’s not that simple. “What we’re trying to do here is completely novel,” says Pedro Irazoqui, a professor of biomedical engineering at Purdue University, where he’s investigating bioelectronic therapies for epilepsy. Jay Pasricha, a professor of medicine and neurosciences at Johns Hopkins University who studies how nerve signals affect obesity, diabetes and gastrointestinal-motility disorders, among other digestive diseases, says, “What we’re doing today is like the precursor to the Model T.”

The biggest challenge is interpreting the conversation between the body’s organs and its nervous system, according to Kris Famm, who runs the newly formed Bioelectronics R. & D. Unit at GlaxoSmithKline, the world’s seventh-largest pharmaceutical company. “No one has really tried to speak the electrical language of the body,” he says. Another obstacle is building small implants, some of them as tiny as a cubic millimeter, robust enough to run powerful microprocessors. Should scientists succeed and bioelectronics become widely adopted, millions of people could one day be walking around with networked computers hooked up to their nervous systems. And that prospect highlights yet another concern the nascent industry will have to confront: the possibility of malignant hacking. As Anand Raghunathan, a professor of electrical and computer engineering at Purdue, puts it, bioelectronics “gives me a remote control to someone’s body.”

Despite the uncertainties, in August, GlaxoSmithKline invested $5 million in SetPoint, and its bioelectronics R. & D. unit now has partnerships with 26 independent research groups in six countries. Glaxo has also established a $50 million fund to support the science of bioelectronics and is offering a prize of $1 million to the first team that can develop an implantable device that can, by recording and responding to an organ’s electrical signals, exert influence over its function. Instead of drugs, “the treatment is a pattern of electrical impulses,” Famm says. “The information is the treatment.” In addition to rheumatoid arthritis, Famm believes, bioelectronic medicine might someday treat hypertension, asthma, diabetes, epilepsy, infertility, obesity and cancer. “This is not a one-trick pony.”

Kevin Tracey, who is 56, came to bioelectronics because of two significant deaths. The first occurred when he was in preschool. He was 5 when his mother died as a result of an inoperable brain tumor. Shortly after the funeral­, Tracey found his maternal grandfather, a professor of pediatrics at Yale, alone in his den. “I climbed onto his lap and asked what happened,” Tracey says. “He explained that surgeons tried to take it out but couldn’t separate the brain-tumor tissue from the normal neurons. I remember saying to him, ‘Somebody should do something about that.’ That was when I decided to be a neurosurgeon. I wanted to solve problems that were insolvable.”

Tracey’s second formative experience took place in May 1985. Having trained for neurosurgery at Cornell, he was on rotation for his residency in the emergency room at New York Hospital when an 11-month-old baby girl named Janice arrived in an ambulance with burns covering 75 percent of her body. Her grandmother was cooking when she tripped and doused Janice with a pot of boiling noodles. After three weeks in the burn unit recovering from skin grafts, Janice appeared to stabilize. Tracey joined Janice’s family to celebrate her first birthday in her hospital room. Janice was upbeat, smiling and giggling. The next day, she was dead.

“I was haunted by her case,” Tracey says. When the autopsy report was inconclusive, Tracey redirected his energy into medical research, specifically inflammation related to sepsis, which he believed contributed to Janice’s unexpected death. Sepsis occurs when the immune system goes into overdrive, producing a potentially lethal inflammatory response to fight a severe infection. At the time of her death, however, Janice did not have an infection. It took another year to figure out that it was an overproduction of tumor necrosis factor — the catalyst for inflammation — that caused Janice’s septic shock, though her death remains a mystery.

Kevin Tracey, a neurosurgeon, studies the effects of stimulating nerves with electricity to fight disease. Credit Katherine Wolkoff for The New York Times

“Her brakes had failed,” Tracey says. “She made too much T.N.F. The obvious question was, why?” He credits Linda Watkins, a neuroscientist at the University of Colorado, Boulder, for furnishing the pivotal clue. In the mid-1990s, Watkins was exploring possible neural connections between the brain and the immune system in rats by injecting them with cytokines — molecules that, like tumor necrosis factor, contribute to inflammation — to cause fevers. But when she cut their vagus nerves, the fever never materialized. Watkins concluded that the vagus nerve must be the conduit through which the body signals the brain to induce fever.

Tracey followed her lead by giving mice a toxin known to cause inflammation and then dosing them with an anti-inflammatory drug he had been investigating. “We injected it into their brains in teeny amounts, too small to get into their bloodstream,” he says. The drug did what it was supposed to do: It halted the production of tumor necrosis factor in the brain. Surprisingly, it also halted the production of tumor necrosis factor in the rest of the body. When Tracey cut the vagus nerve, however, the drug had no effect in the body.

“That was the eureka moment,” he says. The signal generated by the drug had to be traveling from the brain through the nerve because cutting it blocked the signal. “There could be no other explanation.”

Tracey then wondered if he could eliminate the drug altogether and use the nerve as a means of speaking directly to the immune system. “But there was nothing in the scientific thinking that said electricity would do anything. It was anathema to logic. Nobody thought it would work.”

After that first surgery on the rat in 1998, Tracey spent 11 years mapping the neural pathways of tumor-necrosis-factor inflammation, charting a route from the vagus nerve to the spleen to the bloodstream and eventually to mitochondria inside cells. “We now know more about this electrical circuit to treat [inflammation] than is known about some clinically approved drugs,” Tracey says.

By 2009, SetPoint felt ready to test Tracey’s work on people with rheumatoid arthritis, and Ralph Zitnik was approached about joining the company. “It was nuts,” Zitnik told me. “Sticking something on the vagus nerve to take away R.A.? People would think it’s witchcraft.” Zitnik’s background was in pharmaceuticals; at Amgen, he contributed to the development of Enbrel, a rheumatoid-arthritis drug that had $4.7 billion in sales last year, which made it No. 7 on the industry’s best-seller list. But the more he talked with Tracey and pored over the research, the more he said to himself: “There is good science behind this. I thought, This could work.”


SHOCK TREATMENT - VAGUS NERVE IMPLANT POD MAY 20, 2014 Illustration by Clint Ford

During a 20-minute operation, a neuVAGUS NERVE IMPLANT POD MAY 20, 2014 Illustration by Clint Fordrosurgeon will slide SetPoint Medical’s bioelectronic implant onto the vagus nerve on the left side of a patient’s neck, and then snap on an outer housing called the Pod to hold the device in place. Once the implant is activated, electrical impulses transmitted from the implant will communicate directly with immune cells in the spleen and the gastrointestinal tract, inducing them to reduce the production of cytokines — molecules that are involved in inflammation. To recharge the device’s batteries and update its software, patients and physicians will use an iPad app to control a wearable collar that transmits power and data wirelessly through the skin.



Zitnik’s first task at SetPoint was to recruit a lead scientist to set up a clinical trial. Many scientists in the United States and Europe were hesitant to do it, he says, but eventually he hired Paul-Peter Tak, a well-regarded immunologist and rheumatologist based at the Academic Medical Center, the University of Amsterdam’s teaching hospital. “He was a forward-thinking person willing to try an unconventional approach like this,” Zitnik says. Tak in turn hired Frieda Koopman, who was working on her Ph.D. in rheumatology at A.M.C., to find potential patients in the Netherlands and elsewhere in Europe.

The day after an article about the planned trial appeared in a Dutch newspaper, Koopman’s office got more than a thousand calls from rheumatoid-arthritis patients begging to participate. “We never saw that coming,” Koopman says. “We thought we might get one or two patients to join, and wouldn’t that be nice.” Invasive surgery was involved, after all. Koopman’s team returned almost every call and selected several subjects based on what medications they had tried and the severity of the pain and swelling in their joints. Over the next two years, her team continued to enroll new patients.

The subjects in the trial each underwent a 45-minute operation. A neurosurgeon fixed an inchlong device shaped like a corkscrew to the vagus nerve on the left side of the neck, and then embedded just below the collarbone a silver-dollar-size “pulse generator” that contained a battery and microprocessor programmed to discharge mild shocks from two electrodes. A thin wire made of a platinum alloy connected the two components beneath the skin. Once the implant was turned on, its preprogrammed charge — about one milliamp; a small LED consumes 10 times more electricity — zapped the vagus nerve in 60-second bursts, up to four times a day. Typically, a patient’s throat felt constricted and tingly for a moment. After a week or two, arthritic pain began to subside. Swollen joints shrank, and blood tests that checked for inflammatory markers usually showed striking declines.

Koopman told me about a 38-year-old trial patient named Mirela Mustacevic whose rheumatoid arthritis was diagnosed when she was 22, and who had since tried nine different medications, including two she had to self-inject. Some of them helped but had nasty side effects, like nausea and skin rashes. Before getting the SetPoint implant in April 2013, she could barely grasp a pencil; now she’s riding her bicycle to the Dutch coast, a near-20-mile round trip from her home. Mustacevic told me: “After the implant, I started to do things I hadn’t done in years — like taking long walks or just putting clothes on in the morning without help. I was ecstatic. When they told me about the surgery, I was a bit worried, because what if something went wrong? I had to think about whether it was worth it. But it was worth it. I got my life back.”

In February, I met Moncef Slaoui, Glaxo’s chairman of Global Research and Development, at one of the company’s 16 facilities he oversees worldwide, this one in King of Prussia, Pa. Slaoui, who is 55 and has a Ph.D. in molecular biology and immunology, was instrumental in developing the first malaria vaccine and is considered one of the most influential executives in the pharmaceutical industry.

“When Kris came to me in early 2012 with this idea of vagus nerve stimulation,” Slaoui told me, “I was like: C’mon? You’re gonna give a shock and it changes the immune system? I was very skeptical. But finally I agreed to visit Kevin’s lab. I wanted the data, the evidence. I don’t like hot air.” He went to Tak, the lead scientist for the trials. “I asked him, ‘Paul-Peter, is it really real?’ ”


SetPoint Medical’s new neural implant (currently being tested on animals). Credit Katherine Wolkoff for The New York Times

After getting an endorsement from Tak, who is now Glaxo’s global head of immuno-inflammation research, Slaoui committed to financing SetPoint. The investment was modest, though, because he felt that Tracey’s device was “just a starting point. It was still very broad — you touch the vagus nerve, you touch most of your viscera. We had wanted something very specific.” What he didn’t want was “the bulldozer approach” that characterizes already existing stimulators for treating Parkinson’s, chronic pain and epilepsy. (Pacemakers differ because they stimulate muscle, not nerves.) These devices are indiscriminate, blasting electricity into billions of neurons and hoping for the best. As Slaoui saw it, SetPoint’s stimulator was a primitive forerunner to “a device that reads your electrical impulses and sees when something is wrong, then corrects what needs correcting.”

In 2006, Slaoui continued, “when I became chairman of R. & D., R. & D. was a liability to this company. We were spending lots of money and not producing new molecules for new medicines. I had to acknowledge that the current way of doing R. & D. wasn’t likely to be successful.” Four years later, Slaoui put together a 14-member think tank and discussed, among other topics, the Human Brain Project. The multinational endeavor, directed by the neuroscientist and Fulbright scholar Henry Markram, at the Swiss Federal Institute of Technology in Lausanne, is trying to create a computer simulation of the human brain. That got Slaoui “thinking about electrical signaling, an opportunity to make medicine — a therapeutic intervention — that’s super highly specific in terms of its geographic position. I’m going to go to the nerve that goes to your kidney and nowhere else, and only to your left kidney, and to a particular area of the left kidney.”

That degree of precision would address one of Slaoui’s major criticisms of conventional drugs: They flood the body, and then doctors have to hope that they will perform only where they’re supposed to. “It is really difficult to design a molecule that will only interact where you want it, because it goes everywhere.” The upshot, usually: side effects. Bioelectronics could potentially eliminate those, as well as the costly redundancy involved in the drug-discovery process, in which every promising molecule must be independently evaluated. “There is very little that is transposable from one molecule to the next,” Slaoui said. “You have to redo everything.” Bioelectronics attracted him, he says, because “95 percent of the hardware is the same,” no matter what disease it treats.

So Slaoui found himself working for a drug company while devoting himself to the idea of treating illness without drugs. In July 2012, he and Famm toured Markram’s facilities in Lausanne. There Markram showed them a 3-D digital visualization on a giant screen of 100,000 synapses actively firing in a mouse brain.

At that moment, Famm says, he and Slaoui realized they were “biting off too much.” Slaoui and Famm concluded that starting with the brain — which seemed logical, given that it’s the body’s C.P.U. — could take decades to yield viable treatments. The human brain’s circuitry, with 100 billion neurons, seemed far too complex. “Why don’t we just skip the brain and go straight to the organs?” Slaoui suggested.

Right then, Slaoui said, “we decided to focus on the peripheral nervous system.” The peripheral nerves link the brain and spinal cord (the central nervous system) to the organs and limbs. Rather than try to fathom the brain — a black box, basically, with its 100 trillion neural connections — Slaoui proposed that they put “an interface between a nerve and the organ with an electrical device.” To eavesdrop on a telephone call, his thinking went, you don’t tap into the switching center and search for the conversation. You go to the line nearest the caller’s location. Compared with the brain, the cablelike bundles that are the peripheral nerves contain vastly fewer fibers — hundreds versus billions.


The brain, with its billions of neurons, seemed far too complex. ‘Why don't we just skip the brain and go straight to the organs?’ someone suggested.

When I joined Famm in Philadelphia in February, he referred to his role as Glaxo’s bioelectronics chief as “like being a missionary.” Famm, who lives in London, was in the U.S. to attend half a dozen meetings with bioelectronics researchers. His challenge is coaxing those from disparate disciplines to embrace a singular vision. Whereas drug discovery primarily involves like-minded thinkers — molecular biologists, chemists, geneticists — bioelectronics calls for alliances between experts in fields that in many cases have little to do with medicine — nanotech, optics, electrical engineering, materials science, computer programming, wireless networking and data mining. At the moment, Famm is focused on getting what he called a “transdisciplinary” group of scientists to agree on how to solve two key technical challenges.

The first is shrinking the hardware. It must be small enough to attach to virtually any nerve yet still have enough battery power and circuitry to run algorithms that generate the patterns of electrical impulses needed to treat various diseases. At the Charles Stark Draper Laboratory in Cambridge, Mass., we met with a team working on miniaturization. Draper is best known for internal navigation systems that guide things like ballistic missiles and spaceships. Bryan McLaughlin, who directs bioelectronics development at Draper, showed me the latest prototype mock-up — a dime-size implant. It’s small, he said, but not nearly small enough. McLaughlin wants to get its electrodes, microprocessor, battery and a wireless transmitter into a device no larger than a jelly bean. “It’s also important to make it closed-loop, with the ability to read and write to the nervous system.” The goal, in other words, is to end up with something that can continuously monitor a patient and then dispense bioelectronic therapy as needed.

The second challenge is devising a method to make sense of signals emanating simultaneously from hundreds of thousands of neurons. Accurate recording and analysis are essential to bioelectronics in order for researchers to identify the discrepancies between baseline neural signals in healthy individuals and those produced by someone with a particular disease. The conventional approach to recording neural signals is to use tiny probes with electrodes inside called patch clamps. A prostate-cancer researcher, for example, could attach patch clamps to a nerve linked to the prostate in a healthy mouse and record the activity. The same thing would be done with a mouse whose prostate had been genetically engineered to produce malignant tumors. Comparing the output from both might allow the researcher to determine how the neural signals differ in cancerous mice. From such data, a corrective signal could be programmed into a bioelectronic device to treat the cancer.

using patch clamps. They can sample only one cell’s activity at a time, and therefore fail to gather enough data to see the big picture. As Adam E. Cohen, who teaches chemistry and physics at Harvard, puts it, “It’s like trying to watch an opera through a straw.”

Cohen, an expert in an emerging field called optogenetics, thinks he can overcome the limitations of the patch clamps. His research is trying to use optogenetics to decipher the neural language of disease. “Getting patch clamps into a single [neuron] is extremely slow and laborious — about an hour per cell,” Cohen told me when I visited his lab recently. “The bigger problem is that [neural] activity comes not from the voices of individual neurons but from a whole orchestra of them acting in relation to each other. Poking at one at a time doesn’t give you the global view.”

Optogenetics arose out of a series of developments in the 1990s. Scientists knew that proteins, called opsins, in bacteria and algae generated electricity when exposed to light. Optogenetics exploits this mechanism. Opsin genes are inserted into the DNA of a harmless virus, which is then injected into the brain or a peripheral nerve of a test subject. By choosing a virus that prefers some cell types over others, or by altering the virus’s genetic sequence, researchers can target specific neurons — cold- or pain-sensing, for example — or regions of the brain known to be responsible for certain actions or behaviors. Next, an optical fiber — a spaghetti-thin glass cable that transmits light from its tip — is inserted through the skin or skull to the site of the virus. The fiber’s light activates the opsin, which in turn conducts an electrical charge that forces the neuron to fire. Researchers have already controlled mouse behavior with optogenetics — inducing sleep and aggression on command.


Instead of drugs, says the man who runs GlaxoSmithKline's bioelectronics research and development, ‘the treatment is a pattern of electrical impulses. The information is the treatment.’

Before opsins can be used to activate neurons involved in specific ailments, however, scientists must determine not only which neurons are responsible for a particular disease but also how that disease communicates with the nervous system. Like computers, neurons speak a binary language, with a vocabulary based on whether their signal is on or off. The specific sequence, interval and intensity of these on-off shifts determine how information is conveyed. But if each disease can be thought of as speaking its own language, then a translator is needed. What Cohen and others recognized was that optogenetics can do that job. So Cohen reverse-engineered the process: Instead of using light to activate neurons, he used light to record their activity.

Cohen showed me his “Optopatch” machine. It consisted of red and blue lasers, mirrors, lenses, a high-speed digital camera, a video projector, a microscope and several quiet cooling fans. After he turned it on, a postdoc fellow who works in his lab, Shan Lou, inserted a petri dish under its microscope. The dish contained 11 live neural cells from mice, harvested from dorsal-root ganglia, which relay sensory input to the brain. Lou added a few drops of capsaicin extract, the irritant in pepper spray, and then turned the camera on for 14 seconds. In that brief period, it snapped 7,000 frames, totaling 12 gigabytes of data. To analyze it, Cohen had written software that searches for patterns by employing techniques developed for digital voice and face recognition. “We also use algorithms and optical tricks derived from astrophysics,” Cohen said. Seconds later, an analysis appeared on Lou’s computer screen. Three of the 11 cells had been identified as firing in response to the capsaicin, indicating that they were pain-sensing neurons. It would have taken Cohen more than a day to record and make sense of that cellular information with a patch clamp. This sort of effort was a step, he said, “toward imaging large numbers of neurons in parallel, hundreds, perhaps thousands.”

Cohen is collaborating with Ed Boyden, a professor of neuroscience at M.I.T. and a pioneer in optogenetics, to develop the so-called closed-loop implant envisioned by Bryan McLaughlin at Draper Labs. Optogenetics, Boyden told me, enables him to “aim light at some subset of cells [without] activating all the stray cells nearby.”

Opsins might point the way to future treatments for all kinds of diseases, but researchers will most likely have to develop bioelectronic devices that don’t use them. Using genetically engineered viruses is going to be tough to get past the F.D.A. The opsin technique hinges on gene therapy, which has had limited success in clinical trials, is very expensive and seems to come with grave health risks.

Cohen mentions two alternatives. One involves molecules that behave like opsins; another uses RNA that converts into an opsinlike protein — because it doesn’t alter DNA, it doesn’t have the risks associated with gene therapy. Neither approach is very far along, however. And “you still face the problem of getting the light in,” he says. Boyden is developing a brain implant with a built-in laser, but Cohen believes an external light source is more likely for most bioelectronics applications.

Surmounting these sorts of technical hurdles “might take 10 years,” Famm figures. That seems somewhat optimistic if you consider Glaxo’s investment so far in bioelectronics. Melinda Stubbee, the company’s director of communications, says it has spent roughly $60 million in the area, a pittance compared with its $6.5 billion in total R. & D. expenditures in 2013. Slaoui, defending the number, said, “Funding of R. & D. is like an investment” — money only flows toward bankable ideas. While he thinks the area shows promise, he seems to want independent researchers to do the legwork before Glaxo buys in further.


‘I think this is the industry that will replace the drug industry,’ says a pioneer in bioelectronics.

At one point, Famm referred to detractors who say bioelectronics is “too risky, will take too long and is maybe even a bit bonkers.” In trying to find some of them, I contacted a number of financial analysts who track Glaxo and the pharmaceutical industry. One, Mark Clark, at Deutsche Bank, said to me in an email: “I know next to nothing about this early-stage technology! I am prepared to bet you will not find a single Glaxo analyst that knows anything about this! Research technologies were a vogue thing to be expert on in the ’90s and tech-bubble years, but we only care about drugs that are actually in the clinical pipeline these days, not how they get there — to be brutally blunt!”

In short, the fledgling bioelectronics industry is nowhere near mature enough for analysts to make meaningful estimates about its revenue potential. But people like Clark will certainly begin paying closer attention if bioelectronics starts to capture even a sliver of the lucrative pharmaceutical market. Drug sales for rheumatoid arthritis alone were $12.3 billion in 2012. That looks like a big opportunity to an outfit like SetPoint.

Yet if large numbers of patients someday choose bioelectronics over drugs, another issue awaits resolution: security. Bioelectronics devices will feature wireless connectivity so they can be fine-tuned and upgraded, “just like the software on your iPhone,” Famm says. And wireless means hackable, an unsettling fact that worries two experts on medical-device security: Niraj Jha, a professor of electrical engineering at Princeton University, and Anand Raghunathan, who runs the Integrated Systems Laboratory at Purdue.

Fears of medical devices being hacked aren’t new. In 2007, Dick Cheney’s cardiologist disabled the wireless functionality in the former vice president’s defibrillator to prevent terrorists from trying to stop his heart. Jha and Raghunathan, along with the lead author, Chunxiao Li, detailed how this might be accomplished in a seven-page paper they wrote, “Hijacking an Insulin Pump,” published in June 2011. The paper described a hack they performed in their lab using inexpensive, off-the-shelf hardware.

According to Jha and Raghunathan, there are no known cases of malicious attacks on medical devices. Nevertheless, Raghunathan says, “Society should be warned about these possibilities.” The Department of Homeland Security is no doubt worried, addressing the potential threat in an alert it issued last June. In August, the F.D.A. offered guidelines to medical-device manufacturers, recommending “wireless protection” to reduce “risks to patients from a security breach.” Whether bioelectronics developers do anything to thwart hacking (the F.D.A. guidelines are not mandatory) may ultimately depend on whether Jha and Raghunathan’s fears are realized.

Draper’s McLaughlin doesn’t dismiss these concerns but notes that there is no “incentive for device companies to do anything about security.” He adds: “Nobody has been sued. No patient has died. But the first event that occurs with one of these devices — companies will jump on it and create secure platforms.”

SetPoint’s chief technology officer is Mike Faltys, a medical engineer who was integral to designing the modern cochlear implant. Faltys worked for six years out of his garage, first re-engineering an existing electrical stimulator, used to stop seizures, that became the device implanted in patients in SetPoint’s trial, and more recently finishing a significantly more advanced implantable unit that he calls “the microregulator.”

Housed in a pod shaped like a hot-dog bun and the size of a multivitamin, the entire microregulator is entirely self-contained — onboard battery, microprocessor and electrodes are integrated into a single unit. It can be wirelessly recharged, and adjusted and updated with an iPad app. The surgery to clamp it onto the vagus nerve will take about 20 minutes, and once in place, it will provide pain relief to a rheumatoid-arthritis patient for a decade or more before it needs servicing.

On one occasion during my travels with Famm, I got to hold SetPoint’s newfangled microregulator. For now, it’s only capable of transmitting very crude signals to communicate with the nervous system — more like grunts and groans rather than the precise vocabulary that Slaoui envisions for bioelectronic therapies. Even so, the microregulator felt elegant and powerful and promising in my palm. “A patient gets a device like this implanted once for one disease, and they’re done,” Tracey says. “No prescriptions, no medicines, no injections. That’s the future. That’s what gets me out of bed in the morning.”

Michael Behar writes about science and the environment. His work has appeared in “The Best American Travel Writing” and “The Best American Science and Nature Writing.”


Friday, May 23, 2014

Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

Medgadget Exclusive / Neurology

Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

by Tom Fowler on May 22, 2014 • 6:05 pm


vagus nerve stimulation 293x300 Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

electroCore, a Basking Ridge, New Jersey company co-founded in 2005, is developing non-invasive Vagus Nerve Stimulation (nVNS) therapies which can be delivered using their proprietary gammaCore technology to treat various neurologic, psychiatric, gastric motility, and respiratory conditions. Founded on the pioneering concept of using vagal neuromodulation to acutely treat patients with severe bronchoconstriction during an asthma attack, electroCore has used this concept to expand beyond the acute emergency indications and produce a prophylactic vagus nerve stimulation therapy option. Their initial focus on asthma expanded quickly into migraine and cluster headaches, based on patient feedback from their early studies, and new trials are continuing to investigate new uses for nVNS for gastric motility, pain, and sleep disorders, as well as depression and anxiety. I asked co-founder and CEO J.P. Errico about their gammaCore product, the technology behind it, and his role at electroCore.

Tom Fowler, Medgadget: Tell us how you progressed from being an MIT aeronautical engineering student to a patent attorney to leading a medical device company.

JP Errico CEO Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

J.P. Errico: I was strongly influenced by my parents, one who was a practicing physician, and the other who had a law degree, to go, professionally, beyond my initial training as an engineer,. So, after graduating from MIT, I went to Duke Law School, where I branched out and simultaneously received a graduate degree in engineering. Because of my focus on patent law, after graduation I was approached by a family member who was a prominent spine surgeon, and within a very short time, our inventive and entrepreneurial bent had us building the first of several healthcare companies. The ventures were largely centered on inventions that could be licensed to market leading companies. The next stage was to begin the clinical development of more innovative technologies, but again these were purchased away from us by the same sort of market leaders. These ventures were successful in generating more than $500 million for our close network of investors. With electroCore, and nVNS, we are committed to building a ground breaking, paradigm-shifting product line. And with recent developments in our clinical and product design programs, I am increasingly confident of our ability to do just that.

Medgadget: How do you foresee gammaCore transforming the standard of care for headache treatment?

J.P. Errico: I foresee physicians, who have as their first obligation to do no harm, offering gammaCore as a first line treatment for their patients. As one of the world leading headache specialist said; “Why would you not use gammaCore first?” I think he is spot on. Through everything we have done, nVNS with gammaCore has been consistently safe, and it is easy for patients to use. Patients can continue with their existing treatments and if it does not work for some of them (nothing works for everyone), they can stop using it. Medications flood the entire body with exogenous chemicals, and thus, invariably have side effects. GammaCore uses the body’s own neural pathways to carry our nVNS therapy, which some refer to as an “electroceutical”, directly to the areas in the brain that release the endogenous chemicals many drug therapies try to modulate. SSRIs, SNRIs, and GABA analogues are some of the largest classes of drugs on the market, and they are designed to alter brain chemistry, and specifically serotonin, GABA, and norepinephrine (also known as noradrenalin). nVNS modulates these same neurotransmitters, but does so without requiring the patient’s liver, kidneys, and other organs to be exposed to foreign chemicals. The other huge benefit, from a patient’s perspective, is that he or she can likely continue with existing medication(s) if they choose, as there have been no observed interactions of nVNS with other treatments, For these reasons and others, electroceuticals is, and will continue to be a rapidly expanding area of healthcare, with GSK starting a new division and investing in multiple bioelectronics companies, and Merck investing in electroCore. I expect many other pharma and medical device companies will follow suit and become involved in this exciting space, and their traditional drugs will, we believe, will slide to the second or third choice… I also believe that patients will demand a non-invasive option that has fewer and more benign side effects than medications as a first option. We expect payors, as well, will appreciate the fact that nVNS can be used both prophylactically and acutely to manage headaches, and with innovative payment options, we hope to make patients and those who hold the purse strings champions of gammaCore.

Medgadget: What is the technology behind gammaCore therapy and are there any risks involved in having patients self administer the nVNS therapy?

J.P. Errico:Vagus Nerve Stimulation was pioneered, twenty-five years ago, by our friends at Cyberonics (Houston, Tx). They were the first to introduce gentle electrical stimulation of the vagus nerve and show that it can selectively stimulate the subset of the nerves in the vagus that have the ability to quiet the surge of activity associated with epileptic seizures. They have recently announced that more than 100,000 patients, world-wide have received their implants, and the profile of safety of their device has been very positive In fact, I believe that the only reason that this therapy option hasn’t climbed the continuum of care from a last resort to front line therapy is the cost and requirement for surgery. GammaCore offers the best of both worlds, the same underlying mechanism of action, without the requirement for surgery and the astronomical cost. In terms of putting it in the hands of patients, I can only say that it takes less time to train a patient to use gammaCore than it takes to train a person to use inhaled medications, and with over 500,000 doses administered to date, we haven’t found any device related adverse events. If the patient doesn’t like it, the therapy can be discontinued in a fraction of a second. In the modern world, we put oxycontin in the hands of patients for headaches, and we feed amphetamines to children with ADHD. Once those pills are ingested, it takes near-heroic efforts to clear those chemicals from the body.

Medgadget: Surgically implanted VNS has been used for some time in the treatment of refractory epilepsy and depression. What is the cost and effect comparison of implants vs. electroCore’s nVNS?

J.P. Errico: Last I heard, Cyberonics was selling their implantable device for over $24,000 in the US. I am not aware of the price point in the EU, or other markets around the world, but of course, that doesn’t include cost of the neurosurgeons’ time, the operating room staff, the anesthesiologist, the long-term maintenance, adjustments, battery replacement, and explanation of the device, if necessary. All of these costs add up to well over $30,000 in the US. Most importantly, VNS doesn’t work for everyone, so the cost for gaining benefits in those for whom it works have to include all the patients in whom it doesn’t (Cyberonics doesn’t give a rebate if the therapy doesn’t work). Reports indicate that 5 years out from the implantation of the device, close to 60% of patients have experienced significant benefit. That means, the real cost for gaining a patient with significant benefit is over $50,000. With gammaCore, while the final pricing of the therapy hasn’t been established, I am very confident to say that we don’t expect payors to commit anywhere near the same amount just to determine in whom the therapy will work. Our goal is to limit the cost of therapy for the payors as closely as can be to just the patients who are gaining the benefit. We are much more like a pharmaceutical in this way, i.e., think of the gammaCore as a bottle of pills containing 300 treatments. When it is used up, it is disposed of and you get another one. Of course, that isn’t quite as socially responsible to the environment – to be tossing things into the garbage all the time – so we intend to introduce reload-able devices that can be refilled with a new prescription, and the fee structure for this would be just like a chronic medication.

Medgadget: You are a named inventor on more than 125 issued US patents, and more than 100 pending patents. What are three tips for those of us that are applying for patents, particularly in the medical device field?

J.P. Errico: This is going to sound corny, but I would say the first thing you want to do is to make sure that whatever it is that you are trying to patent is actually innovative and has potential value to the world. It is an honor to receive a patent, and it is certainly something to be proud of, but they are expensive to obtain, and cost many thousands of dollars to maintain once you’ve gotten them. Make sure it is going to be worth the effort. Second, I would advise people to get an attorney to help. They really do an important service for inventors, and I would NOT suggest to anyone to do it alone. The scope of the patent, and its enforceability are critical to the value they have, so having a professional working with you is critical. Third, and this is specific to the medical field, which is invariably very crowded and intimidating, I would advise anyone with a good idea to commit yourself to your belief. So long as you are not violating the laws of physics, the only thing that stands between you and success is the energy you are willing to expend to make it happen.

divider Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

Link: electroCore…


Tom Fowler Vagus Nerve Stimulation for the Masses: Interview with electroCore CEO J.P. Errico

Tom Fowler

Tom Fowler worked as a programmer in the healthcare IT industry before settling back in school to learn how to become a doctor. He likes to dabble with biotech startups, write postcards to his relatives, and play his ukulele. He was a TEDMED '13 scholar, has published research in biomedical informatics, and continues to advocate for international maternal and child health. Currently in the SELECT MD leadership program at USF Health Morsani College of Medicine.

Wednesday, May 21, 2014

TMS Is Cost-Effective for Treatment Resistant Depression

TMS Is Cost-Effective for Treatment Resistant Depression

by Lauren LeBano

NEW YORK—Transcranial magnetic stimulation (TMS) is a cost-effective option for treating depression in patients who do not benefit from initial antidepressant medication, according to a study presented at the 167th meeting of the American Psychiatric Association. 

In 2008, the U.S. Food and Drug Administration approved TMS for treatment of major depressive disorder. The noninvasive therapy delivers focused magnetic field pulses that stimulate areas of the brain that play a role in mood regulation. 

To assess the economic value of TMS, researchers used a pseudo-randomized comparison of 306 patients treated with TMS (Neurostar TMS Therapy System) and matched patients who were enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. 

The analysis involved comparing weekly failure and improvement rates among the populations as well as classifying clinical outcomes into four depression health states based on QIDS-SR score. 

Using a Markov model, investigators calculated cost and quality-adjusted life years (QALY) expected for each treatment, with the assumption of an average of 28.7 TMS treatments during the acute phase and six treatments during the taper phase. Patients receiving antidepressant treatment were assumed to take a single antidepressant drug for six weeks that could be augmented if they did not remit. 

The Markov model used a two-year time horizon to calculate cost per incremental QALY of TMS compared with antidepressant medications. Reimbursed costs of TMS were estimated at $181 per treatment. 

According to the model, TMS had a mean annual cost of $11,886, compared with a cost of $10,888 for standard antidepressant treatment. 

In addition, the Incremental Cost-Effectiveness Ratio for TMS was $36,383, which is less than the “willingness-to-pay” standard of $50,000. 

Lead author Mark A. Demitrack, MD, commented that the efficacy and safety of TMS contribute to its economic value, even though it costs more in the short term. “Over time, the durability of the benefit of TMS is much better than drug therapy. People are staying well, and they’re not dropping out because of side effects,” he told Psych Congress Network.

He added, “Since depression is a chronic illness, it’s much more important to look not just at the six weeks of benefit. Keeping people well over the long term is the real trick.”  

—Lauren LeBano 


“Health Economics Comparison of TMS and Antidepressant Drugs in the Treatment of Major Depression.” Abstract presented at the American Psychiatric Association Meeting. May 5, 2014

Friday, May 16, 2014

“brave young woman challenged by epilepsy who is probably at this time solely unique in the world”

Herb <>

3:47 PM (18 minutes ago)

to (Redacted)

Dear (Redacted),

Thank you sincerely for sharing some of your case history with me. I would ask if you would allow me to post the below listed information on my blog site in the hope of possibly benefiting someone else?





To the readership of this blog,

I recently have had some very interesting and informative correspondence with an intelligent, adventuresome and brave young woman challenged by epilepsy who is probably at this time solely unique in the world.

As many of you may already know I have for almost 2 decades since Joyce’s involvement with VNS Therapy tirelessly reached out across this planet to physicians and patients of VNS Therapy whether for Depression or Epilepsy to advance my knowledge and understanding of the therapy and its potential side-effects in the hope of better caring for and maintaining Joyce’s wellness and supporting her needs as well as sharing this garnered information with others.

In doing so I have learned from those implanted as well as explanted patients and from patient(s) who have implanted two (2) neuro-modulation devices such as VNS and heart pacemakers as well as explanted VNS patient(s) who have gone on to obtain DBS.  I now inform you of an even more unique situation.

In this instance I bring to your attention and knowledge a patient who is currently implanted for purposes of seizure control both with VNS and DBS* devices.  From my understanding VNS worked reasonably well, for a time, but by the nature of her illness it was decided additional control was necessary and hence the two prosthesis.  It is also my understanding that she is currently doing reasonably well.

*DBS is not currently FDA approved for epilepsy or depression.

This young woman was kind enough to correspond with me and to answer the questions which I put forth to her and by way of this posting I would like to express my appreciation and deeply thank her for taking the time to share this information with me and I in turn as I continue my efforts to share this unique information with you..

As always, I wish this young woman and all who are challenged; wellness and all the good you’d wish for yourselves and others.



Joyce and Herbert Stein

1008 Trailmore Lane

Weston, FL 33326-2816

(954) 349-8733




4:04 PM (1 minute ago)

to me

That is very well written and kind-hearted in the form you have it. I am happy to provide my experience and knowledge with the DBS and the VNS to you and others who are seeking the information.



Tuesday, May 13, 2014

Doctors Treat Depression With Brain Magnets

Doctors Treat Depression With Brain Magnets

8:00 AM ET


SCIEPRO—Getty Images/Brand X

What to do when the drugs don't work

Meghan McGill was a freshman in college when she was diagnosed with depression. She lost interest in reading and dancing, two of her favorite activities, and eventually missed so many classes that she was disqualified from her university. Six years later, when she was 28, she finally saw a psychiatrist who put her on Prozac. That didn’t help either. “I lost a lot of jobs because I couldn’t call into work,” she says.

McGill’s experience is a familiar one for many patients with depression; more than one in 10 Americans take antidepressants according to the Center for Disease Control—and almost 15% of all women. But 20-40% of people cannot tolerate the side effects or do not benefit from antidepressants.

That’s why doctors are encouraged by a bizarre and novel treatment called transcranial magnetic stimulation (TMS), in which magnets (yes, magnets) are administered to alleviate depression. This strange strategies may provide a way to finally bring relief to patients like McGill, who don’t respond to antidepressant medications or who prefer non-drug treatments for their depression.

Last week, scientists presented their latest success with TMS at the 167th American Psychiatric Association Annual Meeting in New York City. TMS was approved by the FDA in 2008 for the treatment of depression and unlike electroconvulsive therapy (ECT), which uses electrical currents to stimulate the brain to treat serious mental illness like bipolar disorder, TMS does not spur seizures.

The researchers, led by Dr. Mark Demitrack, the chief medical officer of Neuronetics, Inc. and Dr. Kit Simpson of Medical University of South Carolina, studied 306 patients with major depressive disorder who were treated with a TMS device called the NeuroStar TMS Therapy®. (Neurostar was the first TMS therapy on the market, and in 2013, the FDA approved another TMS device called Brainsway.) After one year, people who received six weeks of daily TMS, which targeted the mood regions of the brain, 53% reported no or mild depression. After a comparable period of time, only 38% of people on antidepressants reported the same benefit.

“I think TMS is a very valuable addition to our treatment,” says Dr. Amit Anand, the vice chair for at the Center for Behavioral Health at Cleveland Clinic. Anand was not involved in the research. “It’s a way to treat depression directly, with few side effects. Other research has shown only a small percentage of people respond to it, but I think if even a quarter of those people respond, it’s a benefit.”

Dr. Anand says the Cleveland Clinic will soon be offering the service, which he sees as an option that lies somewhere between antidepressants and ECT. “I think it’s best for people who cannot tolerate antidepressants due to side effects,” he says. “It is does give people hope, but I think expectations should be realistic.”

Dr. Demitrack says TMS comes in when doctors and patients are looking for a second option. “The next option would be the addition of another medication, or they might be recommended to receive Electroconvulsive therapy (ECT), which is more invasive and complicated.” Instead, they could try TMS.

In TMS therapy, a large magnet is put to the left side of the patient’s head. Magnetic pulses are thought to stimulate areas of the patient’s brain that are underactive and are involved in mood regulation. The patient is awake and alert the entire time. The are few side effects other than occasional headaches.

TMS, however, is $998 more expensive than drug therapy, but since it’s a limited-time treatment, the company argues it in two years it is more affordable than additional rounds of drug therapy. Insurance companies are starting to pay for the treatment. (The study was conducted by and for the medical device company, Neuronetics, Inc.)

For now, Dr. Demitrack says TMS is only being studied in patients who don’t respond to antidepressants, and not as a first line therapy. Though, he says he could so how one day patients might prefer it as a first line treatment, even though it’s logistically more difficult than drugs. The American Psychiatric Association does not have an official statement on TMS, but it notes that meta-analyses have discovered relatively small to moderate benefits from TMS.

Encouraging results may help more patients like McGill to finally free themselves from their worst depressive symptoms. “At the second week of treatment, I was suddenly singing to the radio in my car,” she says. “I realized how very different I felt. I just thought, Wow.”

Friday, May 9, 2014

[Surgical complications of vagal nerve stimulation for intractable epilepsy: findings from 26 cases].

No Shinkei Geka. 2014 May;42(5):419-28.

[Surgical complications of vagal nerve stimulation for intractable epilepsy: findings from 26 cases].

[Article in Japanese]

Shimogawa T1, Morioka T, Shimogawa T, Hamamura T, Hashiguchi K, Murakami N.

Author information
  • 1Department of Neurosurgery, Kyushu Rosai Hospital.

<i>Introduction</i>:Vagal nerve stimulation(VNS)is a less invasive palliative treatment for intractable epilepsy and was approved for use in Japan in July 2010. Surgical complications of VNS such as vagal nerve dysfunction, cardiac arrhythmia with asystole, and vocal cord palsy as well as complications arising from fracture of the leads or generator and infections are well known in the West. The aim of the present report is to describe the surgical complications encountered in our hospital and discuss their countermeasures. <i>Material and Methods:</i>We reviewed the clinical records of 26 patients who underwent VNS therapy between March 2011 and June 2013. The cases involved 17 male and 9 female patients, including 8 children(<15 years of age). <i>Results</i>:Three patients(11.5%)experienced severe bradycardia and cardiac asystole following test stimulations of the vagal nerve with a stainless-steel surgical hook left in place, to extend the operative field. It was believed that the current spread through the hook and stimulated the cardiac branch of the vagal nerve. In an adult patient with severe intellectual disability, inappropriate dermatological therapy for a superficial purulent wound on the neck caused lead infection 10 months postoperatively. In a child with moderate intellectual disability, lead fracture was noted in association with rotation of the pulse generator at one month postoperatively. In the former case, the lead was cut off whilst the electrode and anchoring coil on the vagal nerve remained;the whole VNS system was removed in the latter case. Subfascial implantation of the generator was recommended. In an adult patient, disconnection between the leads and generator head was noted at 10 months postoperatively. <i>Conclusions</i>:During intraoperative test stimulations of the vagal nerve, stainless-steel surgical hooks should be removed to avoid the spread of current. In intellectually disabled patients, the pulse generator should be placed in the subfascial area instead of the subcutaneous area, especially children. The connection between the leads and the generator should be performed with the aid of a microscope, after removal of the fluid and tissue.

[PubMed - in process]
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Worthwhile information and videos relating to ECT


ECT (Electro Convulsive Therapy) is a treatment for severe episodes of major depression, mania, and some types of schizophrenia. It involves the use of a brief, controlled electrical current to produce a seizure within the brain. This seizure activity is believed to bring about certain biochemical changers which may cause your symptoms to diminish or to even disappear. A series of seizures, generally 4-­‐12, given at a rate of two or three per week, is required to produce such a therapeutic effect. Sometimes a smaller or larger number may be necessary.

ECT works by affecting the same transmitter chemicals in the brain that are affected by medications. Although there have been many advances in the treatment of mental disorders in recent years, ECT remains the most effective, fastest and/or safest treatment for many cases, particularly when alternative treatments, usually medications are either not effective or not safe, or when a person is very likely to commit suicide. Your doctor will discuss with you why ECT is being recommended in your case and what alternative treatments may be available. ECT is most effective in major depression, where it has a strong beneficial effect to patients. Still there is no guarantee that ECT, or for that matter, any treatment will be effective.

All treatments have risks and side effects; however, not treating your depression also carries potentially significant risks. Prior to ECT patients will undergo a careful medical, psychiatric and laboratory evaluation to make sure that the treatments can be administered in the safest, most effective manner possible. Medications may be adjusted to minimize the risk and maximize the effectiveness of the treatments. For most patients the side effects of ECT are relatively minor.

An overall assessment of the nation’s largest real-world study of treatment –resistant depression (STAR*D, funded by NIMH) suggests that a patient with persistent depression can get well after trying several treatment strategies, but his or her odds of beating the depression diminish as additional treatment strategies are needed.

The results show that 50% of patients fail to achieve remission from depression despite four phases of sequenced treatments. However, ECT provides a 50% to 60% response rate in patients who have not responded to one or more adequate antidepressant trials. (Prudic et al. 1996; Sackeim et al. 1990, 2000).

ECT General Overview Video (View the video)

ECT Technical Overview Video (View the video)


Articles on ECT

TMS Cost-effective for Resistant Depression

Medscape Medical News > Conference News

TMS Cost-effective for Resistant Depression

Megan Brooks

May 07, 2014

NEW YORK ― Transcranial magnetic stimulation (TMS) is a cost-effective treatment option for patients with resistant major depressive disorder (MDD), according to a new economic analysis.

"It's mainly cost-effective because it's not really that much more expensive than drug therapy, and it has a very large improved effect over drug therapy," Kit Simpson, DrPH, professor of health and science research, Medical University of South Carolina, in Charleston, told Medscape Medical News.

The findings were presented here at the American Psychiatric Association's 2014 Annual Meeting.

The analysis focused on the NeuroStar TMS system (Neuronetics, Malvern, Pennsylvania), a noninvasive therapy that delivers MRI-strength pulsed magnetic fields to induce an electric current in a localized region of the cerebral cortex.

It was approved by the US Food and Drug Administration (FDA) in October 2008 for the treatment of antidepressant-resistant MDD, as reported by Medscape Medical News at that time.

Prior studies have shown that TMS can provide long-lasting relief of antidepressant-resistant MDD and significantly improve patients' quality of life (QoL) and functional status.

Dr. Simpson and colleagues conducted a cost-utility analysis using data from prior studies using the NeuroStar TMS system.

They used propensity score matching to create a "pseudo-randomized comparison" between 307 patients who had TMS and an equal number treated with medication in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

For TMS patients, the model assumed an average of 29 acute treatment sessions plus 6 sessions during the taper phase at $181 per session. For STAR*D patients, the model assumed use of a single antidepressant drug for 6 weeks plus augmentation for nonremitters.

The analysis showed that TMS provides an incremental cost-effectiveness ratio of $36,383 per quality-adjusted life-year (QALY), which is less than the usually accepted "willingness-to-pay" standard of $50,000 and shows that it is "good value for money," Dr. Simpson said.

In the model, the mean average annual costs are $11,886 for TMS and $10,888 for STAR*D patients (medication) ― an added cost per year for TMS of $998.

The researchers also calculated the payment per member per month (PMPM) cost for a moderate-sized payor comprising 6 million covered lives and assuming a 2% incidence of patients failing to benefit from initial medication and a utilization of TMS of 15% among these patients.

Under these conditions, the PMPM cost increment was $0.25 during a 2-year period of treating a patient with TMS compared with drug therapy, the researchers say.

This analysis shows that TMS is "cost-effective compared to standard drug treatment" for treatment-resistant MDD, Dr. Simpson told Medscape Medical News.

She noted that these are treatment-resistant patients are "who are very sick and who would normally otherwise be on 2 or 3 antidepressant drugs, and in many cases that still doesn't work. They really have no other options except electroshock therapy, which has side effects, while TMS has no real side effects."

Dr. Simpson said she would like to "see more patients treated with this, but it's a fairly new treatment, and many patients still just go to their primary care doctor and get a prescription for an SSRI [selective serotonin reuptake inhibitor]."

The study was supported by funding from Neuronetics, Inc. Dr. Simpson reports no relevant financial relationships.

American Psychiatric Association's 2014 Annual Meeting. Abstract NR8-66. Presented May 6, 2014.

You Can Treat Depression With Magnets — But Scientists Have No Idea How It Works

You Can Treat Depression With Magnets — But Scientists Have No Idea How It Works


  • May 7, 2014, 12:11 PM

TMS brain chart Neurostar


A schematic showing how TMS stimulates the left prefrontal cortex, activating areas deeper in the brain.

Drugs are the most common psychiatric treatment for depression. But about 40 percent of people fail to respond to this first-line of antidepressants. What to do? The answer to date has often been more and different drugs.

But transcranial magnetic stimulation (TMS), a technique that can revive activity in neurons in the brain's prefrontal cortex using an electromagnet, has been receiving more attention as a possible treatment for these stubborn cases of depression. In 2008, the FDA approved TMS for this purpose. Data since that point has been promising, but questions remain: How does it compare to antidepressant drugs? Is it cost-effective?

Research presented today (May 6) at the American Psychiatric Association's annual meeting in New York suggests that the technique is perhaps better than previously thought. In the study, the researchers compared two groups: those who had received TMS after failing to respond to drugs, and those who were given new antidepressants after not getting better on prior meds. The finding: 53 percent of those receiving TMS had no or mild depression after six weeks of treatment, compared with 38 percent taking a new or augmented type of antidepressant.

The study also looked at the economics. It found that TMS therapy would cost about $1,000 per patient per year, which is considered quite affordable, according to study co-author Kit Simpson, an economist at the Medical University of South Carolina. Over the course of two years, TMS would actually become more affordable than the current default of additional rounds of drug therapy, said Dr. Mark Demitrack, a study co-author and chief medical officer of Neuronetics, which makes a widely-used type of TMS called the NeuroStar TMS Therapy System.

The data seems to suggest that TMS 'might be more effective than drugs.'

The results show the technique is better than drugs for this type of depression, Dr. Demitrack told Popular Science.

"Until now there has been a lot of research showing its efficacy but mostly compared to placebo, not other treatments," said Paul Fitzgerald, a researcher at Monash University in Melbourne, Australia, who wasn't involved in the study. "It is clearly very safe, better tolerated than medication and now the data seems to suggest that it might be more effective."

But there are some caveats. It should first be noted that this was not was not a randomly-assigned, placebo-blind study, the gold standard in gauging how effective treatments are, said Dr. Philip Janicak, at Rush University, who wasn't involved in the research. Rather, it compared two different groups of patients. The first group consisted of 307 patients who were treated with TMS at 42 clinics throughout the U.S., after failing to respond to drugs. The second group, or rather second pool of data, was taken from a previous nationwide study, completed in 2006, of patients who were given new antidepressant medications after failing to respond to previous drug therapy. The patients in the latter group were chosen to match the former group as closely as possible, on measures such as sex, age, severity of illness, etc.

Another factor to consider is that most (about 90 percent) of the patients receiving TMS were still taking their old antidepressants, Dr. Janicak added.

That said, Dr. Janicak has been treating patients with TMS for 15 years, and has seen the technique turn around people's lives. "I have to say I am amazed... we are seeing very significant improvements in these patients," he told Popular Science. Dr. Janicak's work has shown that about 55 to 60 percent of patients who have failed to respond to antidepressants respond to this technique, and see at least a 50 percent improvement in measures of their depression. About 35 percent of those patients have "remitted," with enormous reductions in measures of depression, and some are no longer clinically depressed.

In TCM therapy, an electromagnet is applied to the left side of the forehead. This induces currents in neurons in the left prefrontal cortex--where brain imaging studies have shown a deficit in activity in depressed patients. It is thought that this can induce activity and blood flow to this area, but also causes changes in areas deeper in the brain (responsible for mood regulation) to which neurons in the cortex connect. Side effects of TCM tend to be mild, especially compared to antidepressants, and the most common complaint is a mild headache, Simpson said.

Exactly how TCM works is a mystery, Dr. Janicak said. But the same can be said of antidepressants, he added.

This article originally appeared on Popular Science.