New technique for deep brain stimulation surgery proves accurate and safe

Surgery has been used for Parkinson’s disease and familial tremors, and also shows promise for other disorders

The surgeon who more than two decades ago pioneered deep brain stimulation surgery in the United States to treat people with Parkinson’s disease and other movement disorders has now developed a new way to perform the surgery — which allows for more accurate placement of the brain electrodes and likely is safer for patients.

The success and safety of the new surgical technique could have broad implications for deep brain stimulation, or DBS, surgery into the future, as it may increasingly be used to help with a wide range of medical issues beyond Parkinson’s disease and familial tremors.

The new surgery also offers another distinct advantage: patients are asleep during the surgery, rather than being awake under local anesthesia to help surgeons determine placement of the electrodes as happens with the traditional DBS surgery.

A study detailing the new surgical technique is being published in the June 2013 edition of the Journal of Neurosurgery, and has been published online at the journal’s website.

"I think this will be how DBS surgery will be done in most cases going forward," said Kim Burchiel, M.D., F.A.C.S., chair of neurological surgery at Oregon Health & Science University and the lead author of the Journal of Neurosurgery article. “This surgery allows for extremely accurate placement of the electrodes and it’s safer. Plus patients don’t need to be awake during this surgery — which will mean many more patients who can be helped by this surgery will now be willing to consider it.”

DBS surgery was first developed in France in 1987. Burchiel was the first surgeon in North America to perform the surgery, as part of a Food and Drug Administration-approved clinical trial in 1991.

The FDA approved the surgery for “essential tremor” in 1997 and for tremors associated with Parkinson’s disease in 2002. The surgery has been performed tens of thousands of times over the last decade or so in the United States, most often for familial tremor and Parkinson’s disease. Burchiel and his team at OHSU have performed the surgery more than 750 times.

The surgery involves implanting very thin wire electrodes in the brain, connected to something like a pacemaker implanted in the chest. The system then stimulates the brain to often significantly reduce the tremors.

For most of the last two decades, the DBS patient was required to be awake during surgery, to allow surgeons to determine through monitoring the patient’s symptoms and getting other conscious patient feedback whether the electrodes were placed in the right spots in the brain.

But the traditional form of the surgery had drawbacks. Many patients who might have benefitted weren’t willing to undergo the sometimes 4 to 6 hour surgery while awake. There also is a small chance of hemorrhaging in the brain as the surgeon places or moves the electrodes to the right spot in the brain.

The new technique uses advances in brain imaging in recent years to place the electrodes more safely, and more accurately, than in traditional DBS surgery. The surgical team uses CT scanning during the surgery itself, along with an MRI of the patient’s brain before the surgery, to precisely place the electrodes in the brain, while better ensuring no hemorrhaging or complications from the insertion of the electrode.

The Journal of Neurosurgery article reported on 60 patients who had the surgery at OHSU over an 18-month period beginning in early 2011.

"What our results say is that it’s safe, that we had no hemorrhaging or complications at all — and the accuracy of the electrode placement is the best ever reported," Burchiel said.

Burchiel and his team have done another 140 or so surgeries with the new procedure since enrollment in the study ended. OHSU was the first center to pioneer the new DBS procedure, but other surgical teams across the U.S. are learning the technique at OHSU, and bringing it back to their own centers.

The positive results with the new DBS technique could have ramifications as medical researchers nationwide continue to explore possible new uses for DBS surgery. DBS surgery has shown promising results in clinical trials with some Alzheimer’s patients, with some forms of depression and even with obesity.

If the early promising results for these conditions are confirmed, the number of people who might be candidates for DBS surgery could expand greatly, Burchiel said.

The length of the new surgery for the 60 patients involved in the study was slightly longer than traditional DBS surgery. But as Burchiel and his team have developed the new surgical technique, the new DBS surgeries are usually much shorter, often taking half the time of the more traditional approach. Given that, and that the electrodes are placed more accurately and the surgery is cheaper to perform, the new DBS surgery likely will be the technique most surgeons will use in coming years, Burchiel said.

DBS surgery often helps significantly reduce tremors in patients with familial tremor and tremors and other symptoms in Parkinson’s disease. A parallel study is ongoing at OHSU to assess how symptoms of the patients have improved since their DBS surgery using this new method.

(Image: Dr Frank Gaillard)

A 20-minute bout of yoga stimulates brain function immediately after

Researchers report that a single, 20-minute session of Hatha yoga significantly improved participants’ speed and accuracy on tests of working memory and inhibitory control, two measures of brain function associated with the ability to maintain focus and take in, retain and use new information. Participants performed significantly better immediately after the yoga practice than after moderate to vigorous aerobic exercise for the same amount of time.

The 30 study subjects were young, female, undergraduate students. The new findings appear in the Journal of Physical Activity and Health.

“Yoga is an ancient Indian science and way of life that includes not only physical movements and postures but also regulated breathing and meditation,” said Neha Gothe, who led the study while a graduate student at the University of Illinois at Urbana-Champaign. Gothe now is a professor of kinesiology, health and sport studies at Wayne State University in Detroit. “The practice involves an active attentional or mindfulness component but its potential benefits have not been thoroughly explored.”

“Yoga is becoming an increasingly popular form of exercise in the U.S. and it is imperative to systematically examine its health benefits, especially the mental health benefits that this unique mind-body form of activity may offer,” said Illinois kinesiology and community health professor Edward McAuley, who directs the Exercise Psychology Laboratory where the study was conducted.

The yoga intervention involved a 20-minute progression of seated, standing and supine yoga postures that included isometric contraction and relaxation of different muscle groups and regulated breathing. The session concluded with a meditative posture and deep breathing.

Participants also completed an aerobic exercise session where they walked or jogged on a treadmill for 20 minutes. Each subject worked out at a suitable speed and incline of the treadmill, with the goal of maintaining 60 to 70 percent of her maximum heart rate throughout the exercise session.

“This range was chosen to replicate previous findings that have shown improved cognitive performance in response to this intensity,” the researchers reported.

Gothe and her colleagues were surprised to see that participants showed more improvement in their reaction times and accuracy on cognitive tasks after yoga practice than after the aerobic exercise session, which showed no significant improvements on the working memory and inhibitory control scores.

“It appears that following yoga practice, the participants were better able to focus their mental resources, process information quickly, more accurately and also learn, hold and update pieces of information more effectively than after performing an aerobic exercise bout,” Gothe said. “The breathing and meditative exercises aim at calming the mind and body and keeping distracting thoughts away while you focus on your body, posture or breath. Maybe these processes translate beyond yoga practice when you try to perform mental tasks or day-to-day activities.”

Many factors could explain the results, Gothe said. “Enhanced self-awareness that comes with meditational exercises is just one of the possible mechanisms. Besides, meditation and breathing exercises are known to reduce anxiety and stress, which in turn can improve scores on some cognitive tests,” she said.

“We only examined the effects of a 20-minute bout of yoga and aerobic exercise in this study among female undergraduates,” McAuley said. “However, this study is extremely timely and the results will enable yoga researchers to power and design their interventions in the future. We see similar promising findings among older adults as well. Yoga research is in its nascent stages and with its increasing popularity across the globe, researchers need to adopt rigorous systematic approaches to examine not only its cognitive but also physical health benefits across the lifespan.”

Scientists map the wiring of the biological clock

The World Health Organization lists shift work as a potential carcinogen, says Erik Herzog, PhD, Professor of Biology in Arts & Sciences at Washington University in St. Louis. And that’s just one example among many of the troubles we cause ourselves when we override the biological clocks in our brains and pay attention instead to the mechanical clocks on our wrists.

In the June 5 issue of Neuron, Herzog and his colleagues report the discovery of a crucial part of the biological clock: the wiring that sets its accuracy to within a few minutes out of the 1440 minutes per day. This wiring uses the neurotransmitter, GABA, to connect the individual cells of the biological clock in a fast network that changes strength with time of day.

Daily rhythms of sleep and metabolism are driven by a biological clock in the suprachiasmatic nucleus (SCN), a structure in the brain made up of 20,000 neurons, all of which can keep daily (circadian) time individually.

If the SCN is to be a robust, but sensitive, timing system, the neurons must synchronize precisely with one another and adjust their rhythms to those of the environment.

Herzog’s lab has discovered a push-pull system in the SCN that does both. In 2005 they reported that the neurons in the clock network communicate by means of a neuropeptide (VIP) that pushes them to synchronize with one another. And, as they now report in Neuron, these neurons also communicate with GABA that pulls on them weakly, so they are not too tightly coupled.

Together these two networks (VIP and GABA) ensure the clock runs as coordinated, precise timepiece but one that can still adjust its timing to synchronize with the environment.

“We think the neurotransmitter network is there to introduce enough jitter into the system to allow the neurons to resynchronize when environmental cues change, as they do with the seasons,” Herzog says. But, he says, since this biological ‘reset button’ evolved long before mechanical clocks, artificial lights, and high-speed travel, it doesn’t introduce enough jitter to allow us to adjust quickly to the extreme time shifts of modern life, such as flying “backward” (east) through several time zones.

Understanding the push-pull system in the SCN has enormous implications for public health, bearing, as it does, on daylight saving times, shift work, school starting times, medical intern schedules, truck driver hours, and many other issues where the clock in the brain is pitted against the clock in the hand.

Synchronizing the cellular clocks
The “clock” inside each SCN neuron depends on the cyclic expression of a family of genes such as the Period (PER) genes. The expression of these genes and the neuron’s firing rate typically peak at mid-day and fall at night. The gene activity is like the cogs in a clock, and the electrical activity like the hands on the clock.

Each neuron in the SCN keeps time, but because they’re different cells, they have slightly different rhythms. Some run a little bit fast and others a bit slow. If the SCN as a whole is to function as a clock, its neurons need to synchronize with one another.

The goal of the recent work in the Herzog lab has been to figure out how the clock cells are connected to each other. “It wasn’t clear, for example, if each neuron communicated with just a few of its neighbors or with all of them,” Herzog says.

Mark Freeman, a graduate student in the lab, developed a method for recording the firing rate of about 100 neurons simultanously on a multi-electrode array. “You float the SCN neurons down gently,” Herzog says, “and the neurons will attach to the electrodes, creating a clock in a dish that will tick away for weeks or months.”

Using these electrode arrays, his lab demonstrated that the neurons in the SCN are synchronized by the exchange of the neuropeptide VIP (vasoactive intestinal polypeptide), which alters the expression of PER to speed up or slow down neurons until they are all in synch.

These synchronized networks are very precise, says Herzog. If you let them free-run in constant darkness they will lose or gain only a few minutes out of the 1,440 minutes in a day. So they’re accurate to within 1 or 2 percent.

But they’re ever so slightly off the 24-hour cycle tied to one turn of the planet on its axis. Over time they would drift far enough off that cycle to be of little use to us, unless they also had some means of synchronizing to local time.

Resetting the cellular clocks
In the article published in Neuron, Herzog and his colleagues report on a second network in the biological clock.

In this network the connections are made by the neurotransmitter GABA (γ-amino-butyric acid). “We proved we had found a GABAergic network by applying drugs that block GABA receptors on the cells,” Herzog says. “All of the connections we had mapped between neurons dropped out.”

Remarkably, when the network drops out, the clock becomes more precise. So the GABAergic network destabilizes the clock; it jiggles it a little.

Herzog points out that the GABAergic network, is sparse, weak and fast (much faster than the VIP network, which relies on the slower action of a neuropeptide), as you might expect a jitter-generator to be.

“We think the GABAergic network is there to let our clocks adjust to environmental cues, such as gradual, seasonal changes in sunrise and sunset,” says Herzog. 

It’s a bit like whacking an old television set that has lost vertical synch to get it to resynch with the broadcast signal.

But there isn’t enough jitter in the clock to allow it to make abrupt adjustments, such as the one-hour forward jump when Daylight Savings Time starts. That “spring forward” has been statistically shown to increase the likelihood of heart attacks and car accidents, Herzog says.

Some sleep aids, such as benzodiazepines, that activate the GABA receptors may make the circadian clock a little more jittery, helping people adjust to big time jumps, such as flying across time zones. “But we don’t yet know whether they can improve jetlag; if they do, we want to know if it is because they help you sleep on the long flight or because they help the biological clock adjust to the new time zone,” Herzog cautions.

In any case, it is clear that if people repeatedly force the clock to reset, they throw off more than sleep. The biological clock regulates metabolism and cell division as well as sleep/wake cycles. So shift work, for example, is associated both with metabolic disorders, such as diabetes, and with the unregulated cell division that characterizes cancer.

Fighting our biological clocks does a lot more than make us crabby coffee drinkers.

Never forget a face? Researchers find women have better memory recall than men

New research from McMaster University suggests women can remember faces better than men, in part because they spend more time studying features without even knowing it, and a technique researchers say can help improve anyone’s memories.

The findings help to answer long-standing questions about why some people can remember faces easily while others quickly forget someone they’ve just met.

“The way we move our eyes across a new individual’s face affects our ability to recognize that individual later,” explains Jennifer Heisz, a research fellow at the Rotman Research Institute at Baycrest Health Sciences and newly appointed assistant professor in the Department of Kinesiology at McMaster University.

She co-authored the paper with David Shore, psychology professor at McMaster and psychology graduate student Molly Pottruff.

“Our findings provide new insights into the potential mechanisms of episodic memory and the differences between the sexes. We discovered that women look more at new faces than men do, which allows them to create a richer and more superior memory,” Heisz says.

Eye tracking technology was used to monitor where study participants looked—be it eyes, nose or mouth—while they were shown a series of randomly selected faces on a computer screen. Each face was assigned a name that participants were asked to remember.

One group was tested over the course of one day, another group tested over the course of four days.

“We found that women fixated on the features far more than men, but this strategy operates completely outside of our awareness. Individuals don’t usually notice where their eyes fixate, so it’s all subconscious.”

The implications are exciting, she says, because it means anyone can be taught to scan more and potentially have better memory.

“The results open the possibility that changing our eye movement pattern may lead to better memory,” says Shore. “Increased scanning may prove to be a simple strategy to improve face memory in the general population, especially for individuals with memory impairment like older adults.”

Common gene known to cause inherited autism now linked to specific behaviors

The genetic malady known as Fragile X syndrome is the most common cause of inherited autism and intellectual disability. Brain scientists know the gene defect that causes the syndrome and understand the damage it does in misshaping the brain’s synapses — the connections between neurons. But how this abnormal shaping of synapses translates into abnormal behavior is unclear.

Now, researchers at UCLA believe they know. Using a mouse model of Fragile X syndrome (FXS), they recorded the activity of networks of neurons in a living mouse brain while the animal was awake and asleep. They found that during both sleep and quiet wakefulness, these neuronal networks showed too much activity, firing too often and in sync, much more than a normal brain.

This neuronal excitability, the researchers said, may be the basis for symptoms in children with FXS, which can include disrupted sleep, seizures or learning disabilities. The findings may lead to treatments that could quiet the excessive activity and allow for more normal behavior.

The study results are published in the June 2 online edition of the journal Nature Neuroscience.

According to the National Fragile X Foundation, approximately one in every 3,600 to 4,000 males has the disorder, as does one in 4,000 to 6,000 females. FXS is caused by a mutation in the gene FMR1, which encodes the fragile X mental retardation protein, or FMRP. That protein is believed to be important for the formation and regulation of synapses. Mice that lack the FMR1 gene — and therefore lack the FMRP protein — show some of the same symptoms of human FXS, including seizures, impaired sleep, abnormal social relationships and learning defects.

"We wanted to find the link between the abnormal structure of synapses in the FXS mouse and the behavioral abnormalities at the level of brain circuits. That had not been previously established," said senior author Dr. Carlos Portera-Cailliau, an associate professor in the departments of neurology and neurobiology at UCLA. " So we tested the signaling between different neurons in Fragile X mice and indeed found there was abnormally high firing of action potentials — the signals between neurons — and also abnormally high synchrony — that is, too many neurons fired together. That’s a feature that is common in early brain development, but not in the adult."

"In essence, this points to a relative immaturity of brain circuits in FXS," added Tiago Gonçalves, a former postdoctoral researcher in Portera-Cailliau’s laboratory and the first author of the study.

The researchers used two-photon calcium imaging and patch-clamp electrophysiology — two sophisticated technologies that allowed them to record the signals from individual brain cells. Abnormally high firing and network synchrony, said Portera-Cailliau, is evidence of the fact that neuronal circuits are overexcitable in FXS.

"That likely leads to aberrant brain function or impairments in the normal computations of the brain," he said. "For example, high synchrony could lead to seizures; more neurons firing together could cause entire portions of the brain to fire synchronously, which is the basis of seizures."

And epilepsy, Portera-Cailliau said, is seen in up to 20 percent of children with FXS. High firing rates could also impair the ability of the brain to decode sensory stimuli by causing an overwhelming response to even simple sensory stimuli; this could lead to autism and the withdrawal from social interactions, he noted.

"Interestingly, we found that the high firing and synchrony were especially apparent at times when the animals were asleep," said Portera-Cailliau. "This is curious because a prominent symptom of FXS is disrupted sleep and frequent awakenings."

And, he noted, since sleep is important for encoding memories and consolidating learning, this hyperexcitability of brain networks in FXS may interfere with the process of laying down new memories, and perhaps explain the learning disability in children with FXS.

"Because brain scientists know a lot about the factors that regulate neuronal excitability, including inhibitory neurons, they can now try to use a variety of strategies to dampen neuronal excitation," he said. "Hopefully, this may be helpful to treat symptoms of FXS."

The next step, said Portera-Cailliau, is to explore whether Fragile X mice indeed exhibit exaggerated responses to sensory stimuli.

"An overwhelming reaction to a slight sound or caress, or hyperarousal to sensory stimuli, could be common to different types of autism and not just FXS," he said. "If hyperexcitability is the brain-network basis for these symptoms, then reducing neuronal excitability with certain drugs that modulate inhibition could be of therapeutic value in these devastating neurodevelopmental disorders."

Neuroscience Research Project Examines Neural Synchronization Patterns During Addiction

A cross-disciplinary collaboration of researchers in the School of Science at Indiana University-Purdue University Indianapolis (IUPUI) explores the neural synchrony between circuits in the brain and their behavior under simulated drug addiction. The two-year study could have broad implications for treating addiction and understanding brain function in conditions such as Parkinson’s disease.

Advanced mathematical models coupled with extensive laboratory testing revealed recurrent stimulant injections in rodents resulted in neural circuits that could easily synchronize but were more likely to become unstable. In other words, the introduction and restriction of drugs over time caused neurons to lose their ability to engage supervisory control over brain function and behavior. Researchers noticed these short periods of desynchronization were much more prevalent and caused changes in neurobiology and behavior.

“A better understanding of the dynamics of neural synchrony could have very important implications for understanding the addicted brain and may provide a physiological target to understand persistent neural changes that contribute to the probability of relapse,” said Christopher Lapish, Ph.D., assistant professor of psychology at IUPUI.

Lapish, with expertise in neurophysiology and addiction, and Leonid Rubchinsky, Ph.D., associate professor of mathematical sciences, collaborated on the project with support from the IUPUI Institute for Mathematical Modeling and Computational Science. Rubchinsky is an applied mathematician and neuroscientist who has extensively studied the neurophysiology of Parkinson’s disease.

Sungwoo Ahn, Ph.D., a post-doctoral fellow in mathematical sciences, also co-authored the study, recently published in the Cerebral Cortex scientific journal.

The research was patterned after the various stages of drug addiction: the first introduction of amphetamines, periods of abstinence that model withdrawal and then relapse.

The neural synchrony patterns of models injected with a stimulant were compared to those injected with a saline solution. Short periods of desychronization were prevalent in both groups, but the drug-affected group displayed a marked connection between synchrony and brain function. Synchrony has long been considered to play an important role in how the brain processes data, so any disruption of this pattern could hold significant research value, according to the published study.

“Through these long and progressive experimental examinations, we were able to explore the different areas of the brain and how they are connected to each other,” Rubchinsky said. “In addition to understanding, monitoring, diagnosing and treating addiction, this type of study is helpful in better understanding how the normal brain works.”

This collaboration moves scientists closer to understanding brain function and disruptions, Rubchinsky said, by incorporating mathematical models that recreate events and reactions in the brain over time. Lapish agreed, saying computational science ultimately will drive the growth and success of future neuroscience research.

“Neuroscience is an inherently data-rich science and, by combining experimentalists with theorists, there is a tremendous potential for discovery,” Lapish. “The interactive effects of this collaboration are certainly greater than the sum of its parts. We’re able to create a fully dynamic picture of this process that would not be possible without combining these two areas of expertise.”

Moving forward, the team will continue to seek funding to advance their research methods and better understand the role of synchrony in brain function. By doing so, scientists could map the progress and deterioration of neural circuits in various scenarios.