Long-term study reports deep brain stimulation effective for most common hereditary dystonia

In what is believed to be the largest follow-up record of patients with the most common form of hereditary dystonia – a movement disorder that can cause crippling muscle contractions – experts in deep brain stimulation report good success rates and lasting benefits.

Michele Tagliati, MD, neurologist, director of the Movement Disorders Program at Cedars-Sinai Medical Center’s Department of Neurology, and Ron L. Alterman, MD, chief of the Division of Neurosurgery at Beth Israel Deaconess Medical Center in Boston, published the study in the July issue of the journal Neurosurgery. The doctors worked together at two New York City hospitals for a decade, until Tagliati joined Cedars-Sinai in 2010.

The study is focused on early-onset generalized dystonia, which in 1997 was found to be caused by a mutation of the DYT1 gene. Less than 1 percent of the overall population carries this mutation, but the frequency is believed to be three to five times higher among people of Ashkenazi Jewish heritage. Thirty percent of people who carry the defect develop dystonia.

“Long-term follow-up of DYT1 patients who have undergone DBS treatment is scarce, with current medical literature including only about 50 patients followed for three or more years,” Tagliati said. This study reviewed medical records of 47 consecutive patients treated with DBS for at least one year over a span of 10 years, 2001 to 2011.

“We found that, on average, symptom severity dropped to less than 20 percent of baseline within two years of device implantation. Sixty-one percent of patients were able to discontinue all their dystonia-related medications, and 91 percent were able to discontinue at least one class of drugs,” Tagliati said. “Although a few earlier studies found that stimulation’s effectiveness might wane after five years, our observations confirmed what other important DBS studies in dystonia are finding. Patients had statistically and clinically significant improvement that was maintained up to eight years.”

Alterman, the article’s senior author and the neurosurgeon who performed the implant surgeries, said the study also confirmed the procedure’s safety. Complications, such as infection and device malfunction, were rare and manageable.

Patient follow-up ranged from one year to eight years after surgery; 41 patients were seen for at least two years, and four completed eight years. The youngest patient at time of surgery was 8 and the oldest was 71, with a median age of 16.

Dystonia’s muscle contractions cause the affected area of the body to twist involuntarily, with symptoms that range from mild to crippling. If drugs – which often have undesirable side effects, especially at higher doses – fail to give relief, neurosurgeons and neurologists may work together to supplement medications with deep brain stimulation, aimed at modulating abnormal nerve signals. Electrical leads are implanted in the brain – one on each side – and an electrical pulse generator is placed near the collarbone. The device is programmed with a remote, hand-held controller. Tagliati is an expert in device programming, which fine-tunes stimulation for individual patients.

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)

Deep brain stimulation: a fix when the drugs don’t work

Neurological disorders can have a devastating impact on the lives of sufferers and their families.

Symptoms of these disorders differ extensively – from motor dysfunction in Parkinson’s disease, memory loss in Alzheimer’s disease to inescapable cravings in drug addiction.

Drug treatments are often ineffective in these disorders. But what if there was a way to simply switch off a devastating tremor, or boost a fading memory?

Recent advances using Deep Brain Stimulation (DBS) in selective brain regions have provided therapeutic benefits and have allowed those affected by these neurological disorders freedom from their symptoms, in absence of an existing cure.

A pacemaker for the brain

Artificial cardiac pacemakers are typically associated with controlling and resynchronising heartbeats by electrical stimulation of the heart muscle.

In a similar manner, DBS sends electrical impulses to specific parts of the brain that control discrete functions. This stimulation evokes control over the neural activity within these regions.

Prior to switching on the electrical stimulation, electrodes are surgically implanted within precise brain regions to control a specific function.

The neurosurgery is conducted under local anaesthetic to maintain consciousness in the patient. This ensures that the electrode does not damage critical brain regions.

The brain itself has no pain receptors so does not require anaesthetic.

Following recovery from surgery the electrodes are activated and the current calibrated by a neurologist to determine the optimal stimulation parameters.

The patient can then control whether the electrodes are on or off by a remote battery-powered device.

Turning off tremors

Perhaps the most documented success of DBS is in the control of tremors and motor coordination in Parkinson’s disease.

This is caused by the degeneration of neurons in an area of the brain called the substantia nigra. These neurons secrete the neurotransmitter dopamine.

Deterioration of these neurons reduces the amount of dopamine available to be released in a brain area involved in movement, the basal ganglia.

Drug therapy for Parkinson’s disease involves the use of levodopa (L-DOPA), a form of dopamine that can cross the blood brain barrier and then be synthesised into dopamine.

The administration of L-DOPA temporarily reduces the motor symptoms by increasing dopamine concentrations in the brain. However, side effects of this treatment include nausea and disordered movement.

DBS has been shown to provide relief from the motoric symptoms of Parkinson’s disease and essential tremors.

For the treatment of Parkinson’s disease electrodes are implanted into regions of the basal ganglia – the subthalamic nucleus or globus pallidus, to restore control of movement.

These are regions innervated by the deteriorating substantia nigra, therefore the DBS boosts stimulation to these areas.

Patients can then switch on the electrodes, stimulating these brain regions to enhance control of movement and diminish tremors.

Restoring fading memories

Recently, DBS has been used to diminish memory deficits associated with Alzheimer’s disease, a progressive and terminal form of dementia.

The pathologies associated with Alzheimer’s disease involve the formation of amyloid plaques and neurofibrillary tangles within the brain leading to dysfunction and death of neurons.

Brain regions primarily affected include the temporal lobes, containing important memory structures including the hippocampus.

Recent clinical trials with DBS involve the implantation of electrodes within the fornix – a structure connecting the left and right hippocampi together.

By stimulating neural activity within the hippocampi via the fornix, memory deficits associated with Alzheimer’s disease can be improved, enhancing the daily functioning of patients and slowing the progression of cognitive decline.

Deactivating addiction

Another use of DBS is in the treatment of substance abuse and drug addiction. Substance-related addictions constitute the most frequently occurring psychiatric disease category and patients are prone to relapse following rehabilitative treatment.

Persistent drug use leads to long term changes in the brain’s reward system.

Understanding of the reward systems affected in addiction has created a range of treatment options that directly target dysregulated brain circuits in order to normalise functionality.

One of the key reward regions in the brain is the nucleus accumbens and this has been used as a DBS target to control addiction.

Translational animal research has indicated that stimulation of the nucleus accumbens decreases drug seeking in models of addiction. Clinical studies have shown improved abstinence in both heroin addicts and alcoholics.

Studies have extended the use of DBS to potentially restore control of maladaptive eating behaviours such as compulsive binge eating.

In a recent study, binge eating of a high fat food in mice was decreased by DBS of the nucleus accumbens. This is the first study demonstrating that DBS can control maladaptive eating behaviours and may be a potential therapeutic tool in obesity.

Despite its therapeutic use for more than a decade, the neural mechanism of DBS is still not yet fully understood.

The remedial effect is proposed to involve modulation of the dopamine system – and this seems particularly relevant in the context of Parkinson’s disease and addiction.

DBS potentially has effects on the functional activity of other interconnected brain systems. While it can provide therapeutic relief from symptoms of neurological diseases, it does not treat the underlying pathology.

But it provides both effective and rapid intervention from the effects of debilitating illnesses, restoring activity in deteriorating brain regions and aids understanding of the brain circuits involved in these disorders.

Brain implants: Restoring memory with a microchip

William Gibson’s popular science fiction tale “Johnny Mnemonic” foresaw sensitive information being carried by microchips in the brain by 2021. A team of American neuroscientists could be making this fantasy world a reality.

Their motivation is different but the outcome would be somewhat similar. Hailed as one of 2013’s top ten technological breakthroughs by MIT, the work by the University of Southern California, North Carolina’s Wake Forest University and other partners has actually spanned a decade.

But the U.S.-wide team now thinks that it will see a memory device being implanted in a small number of human volunteers within two years and available to patients in five to 10 years. They can’t quite contain their excitement.

"I never thought I’d see this in my lifetime," said Ted Berger, professor of biomedical engineering at the University of Southern California in Los Angeles. "I might not benefit from it myself but my kids will."

Rob Hampson, associate professor of physiology and pharmacology at Wake Forest University, agrees. “We keep pushing forward, every time I put an estimate on it, it gets shorter and shorter.”

The scientists — who bring varied skills to the table, including mathematical modeling and psychiatry — believe they have cracked how long-term memories are made, stored and retrieved and how to replicate this process in brains that are damaged, particularly by stroke or localized injury.

Berger said they record a memory being made, in an undamaged area of the brain, then use that data to predict what a damaged area “downstream” should be doing. Electrodes are then used to stimulate the damaged area to replicate the action of the undamaged cells.

They concentrate on the hippocampus — part of the cerebral cortex which sits deep in the brain — where short-term memories become long-term ones. Berger has looked at how electrical signals travel through neurons there to form those long-term memories and has used his expertise in mathematical modeling to mimic these movements using electronics.

Hampson, whose university has done much of the animal studies, adds: “We support and reinforce the signal in the hippocampus but we are moving forward with the idea that if you can study enough of the inputs and outputs to replace the function of the hippocampus, you can bypass the hippocampus.”

The team’s experiments on rats and monkeys have shown that certain brain functions can be replaced with signals via electrodes. You would think that the work of then creating an implant for people and getting such a thing approved would be a Herculean task, but think again.

For 15 years, people have been having brain implants to provide deep brain stimulation to treat epilepsy and Parkinson’s disease — a reported 80,000 people have now had such devices placed in their brains. So many of the hurdles have already been overcome — particularly the “yuck factor” and the fear factor.

"It’s now commonly accepted that humans will have electrodes put in them — it’s done for epilepsy, deep brain stimulation, (that has made it) easier for investigative research, it’s much more acceptable now than five to 10 years ago," Hampson says.

Much of the work that remains now is in shrinking down the electronics.

"Right now it’s not a device, it’s a fair amount of equipment,"Hampson says. "We’re probably looking at devices in the five to 10 year range for human patients."

The ultimate goal in memory research would be to treat Alzheimer’s Disease but unlike in stroke or localized brain injury, Alzheimer’s tends to affect many parts of the brain, especially in its later stages, making these implants a less likely option any time soon.

Berger foresees a future, however, where drugs and implants could be used together to treat early dementia. Drugs could be used to enhance the action of cells that surround the most damaged areas, and the team’s memory implant could be used to replace a lot of the lost cells in the center of the damaged area. “I think the best strategy is going to involve both drugs and devices,” he says.

Unfortunately, the team found that its method can’t help patients with advanced dementia.

"When looking at a patient with mild memory loss, there’s probably enough residual signal to work with, but not when there’s significant memory loss," Hampson said.

Constantine Lyketsos, professor of psychiatry and behavioral sciences at John Hopkins Medicine in Baltimore which is trialing a deep brain stimulator implant for Alzheimer’s patients was a little skeptical of the other team’s claims.

"The brain has a lot of redundancy, it can function pretty well if loses one or two parts. But memory involves circuits diffusely dispersed throughout the brain so it’s hard to envision." However, he added that it was more likely to be successful in helping victims of stroke or localized brain injury as indeed its makers are aiming to do.

The UK’s Alzheimer’s Society is cautiously optimistic.

"Finding ways to combat symptoms caused by changes in the brain is an ongoing battle for researchers. An implant like this one is an interesting avenue to explore," said Doug Brown, director of research and development.

Hampson says the team’s breakthrough is “like the difference between a cane, to help you walk, and a prosthetic limb — it’s two different approaches.”

It will still take time for many people to accept their findings and their claims, he says, but they don’t expect to have a shortage of volunteers stepping forward to try their implant — the project is partly funded by the U.S. military which is looking for help with battlefield injuries.

There are U.S. soldiers coming back from operations with brain trauma and a neurologist at DARPA (the Defense Advanced Research Projects Agency) is asking “what can you do for my boys?” Hampson says.

"That’s what it’s all about."

Remarkable Success In Patients With Major Depression

For the first time, physicians from the Bonn University Hospital have stimulated patients’ medial forebrain bundles.

Researchers from the Bonn University Hospital implanted pacemaker electrodes into the medial forebrain bundle in the brains of patients suffering from major depression with amazing results: In six out of seven patients, symptoms improved both considerably and rapidly. The method of Deep Brain Stimulation had already been tested on various structures within the brain, but with clearly lesser effect. The results of this new study have now been published in the renowned international journal “Biological Psychiatry.”

After months of deep sadness, a first smile appears on a patient’s face. For many years, she had suffered from major depression and tried to end her life several times. She had spent the past years mostly in a passive state on her couch; even watching TV was too much effort for her. Now this young woman has found her joie de vivre again, enjoys laughing and traveling. She and an additional six patients with treatment resistant depression participated in a study involving a novel method for addressing major depression at the Bonn University Hospital.

Considerable amelioration of depression within days

Prof. Dr. Volker Arnd Coenen, neurosurgeon at the Department of Neurosurgery (Klinik und Poliklinik für Neurochirurgie), implanted electrodes into the medial forebrain bundles in the brains of subjects suffering from major depression with the electrodes being connected to a brain pacemaker. The nerve cells were then stimulated by means of a weak electrical current, a method called Deep Brain Stimulation. In a matter of days, in six out of seven patients, symptoms such as anxiety, despondence, listlessness and joylessness had improved considerably. “Such sensational success both in terms of the strength of the effects, as well as the speed of the response has so far not been achieved with any other method,” says Prof. Dr. Thomas E. Schläpfer from the Bonn University Hospital Department of Psychiatry und Psychotherapy (Bonner Uniklinik für Psychiatrie und Psychotherapie).

Central part of the reward circuit

The medial forebrain bundle is a bundle of nerve fibers running from the deep-seated limbic system to the prefrontal cortex. In a certain place, the bundle is particularly narrow because the individual nerve fibers lie close together. “This is exactly the location in which we can have maximum effect using a minimum of current,” explains Prof. Coenen, who is now the new head of the Freiburg University Hospital’s Department of Stereotactic and Functional Neurosurgery (Abteilung Stereotaktische und Funktionelle Neurochirurgie am Universitätsklinikum Freiburg). The medial forebrain bundle is a central part of a euphoria circuit belonging to the brain’s reward system. What kind of effect stimulation exactly has on nerve cells is not yet known. But it obviously changes metabolic activity in the different brain centers.

Success clearly increased over that of earlier studies

The researchers have already shown in several studies that deep brain stimulation shows an amazing and–given the severity of the symptoms– unexpected degree of amelioration of symptoms in major depression. In those studies, however, the physicians had not implanted the electrodes into the medial forebrain bundle but instead into the nucleus accumbens, another part of the brain’s reward system. This had resulted in clear and sustainable improvements in about 50 percent of subjects. “But in this new study, our results were even much better,” says Prof. Schläpfer. A clear improvement in complaints was found in 85 percent of patients, instead of the earlier 50 percent. In addition, stimulation was performed with lower current levels, and the effects showed within a few days, instead of after weeks.

Method’s long-term success proven

“Obviously, we have now come closer to a critical structure within the brain that is responsible for major depression,” says the psychiatrist from the Bonn University Hospital. Another cause for optimism among the group of physicians is that, since the study’s completion, an eighth patient has also been treated successfully. The patients have been observed for a period of up to 18 month after the intervention. Prof. Schläpfer reports, “The anti-depressive effect of deep brain stimulation within the medial forebrain bundle has not decreased during this period.” This clearly indicates that the effects are not temporary. This method gives those who suffer from major depression reason to hope. However, it will take quite a bit of time for the new procedure to become part of standard therapy.

FYI: Do Lobotomies Work?

Surprisingly, yes.

The modern lobotomy originated in the 1930s, when doctors realized that by severing fiber tracts connected to the frontal lobe, they could help patients overcome certain psychiatric problems, such as intractable depression and anxiety. Over the next two decades, the procedure would become simple and popular, completed by poking a sharpened tool above the eyeball. According to one study, about two thirds of patients showed improvement after surgery.

Unfortunately, not all lobotomy practition-ers were responsible, and the technique left some patients with severe side effects, including seizures, lethargy, changes in personality, and incontinence. In response, doctors refined their techniques. They replaced the lobotomy with more specialized approaches: the cingulotomy, the anterior capsulotomy, and the subcaudate tractotomy. Studies of these procedures found evidence of benefit for at least one fourth of patients suffering from problems such as OCD and depression.

Even with the risk of side effects, those in the field still say the procedures were by and large successful. “I feel that the principle behind ablative surgery was somewhat exonerated by the research findings, which showed that it worked for very specific indications,” says Konstantin Slavin, president of the American Society for Stereotactic and Functional Neurosurgery, and professor at the Uni­versity of Illinois at Chicago.

By the 1980s, lobotomies had fallen out of fashion. “In general, the entire functional neurosurgery field moved away from destruction—from ablative surgery,” Slavin says. A then-new technique called deep-brain stimulation made ablative surgery obsolete. In the procedure, a surgeon drills holes in the head and inserts electrodes into the neural tissue. When current passes through the leads, they activate or inactivate patches of the brain. “The attractive part is that we don’t destroy the tissue,” Slavin says. Doctors can also adjust treatment if a patient suffers side effects. They can turn the current down or suspend it altogether—so as to “give the brain a holiday,” as Slavin calls it.

Most deep-brain stimulation is now used to treat movement disorders such as Parkinson’s Disease. The surgical treatment of patients with OCD is FDA-approved but reserved only for extreme cases. Slavin and his colleagues have been examining broader uses in an ongoing study. “Within the next five years, we hope we’ll have a definitive answer of whether or not it works.”