Posts tagged dystonia
Articles and news from the latest research reports.
3-D Computer Model May Help Refine Target for Deep Brain Stimulation Therapy for Dystonia
Although deep brain stimulation can be an effective therapy for dystonia – a potentially crippling movement disorder – the treatment isn’t always effective, or benefits may not be immediate. Precise placement of DBS electrodes is one of several factors that can affect results, but few studies have attempted to identify the “sweet spot,” where electrode placement yields the best results.
Researchers led by investigators at Cedars-Sinai, using a complex set of data from records and imaging scans of patients who have undergone successful DBS implantation, have created 3-D, computerized models that map the brain region involved in dystonia. The models identify an anatomical target for further study and provide information for neurologists and neurosurgeons to consider when planning surgery and making device programming decisions.
“We know DBS works as a treatment for dystonia, but we don’t know exactly how it works or why some patients have better, quicker results than others. Patient age, disease duration and other underlying factors have a role, and we believe electrode positioning and device programming are critical, but there is no consensus on ideal device placement and optimal programming strategies,” said Michele Tagliati, MD, director of the Movement Disorders Program in the Department of Neurology at Cedars-Sinai.
“This modeling paves the way for the construction of practical therapeutic and investigational targets,” added Tagliati, senior author of an article now available on the online edition of Annals of Neurology.
Medications usually are the first line of treatment for dystonia and several other movement disorders, but if drugs fail – as frequently happens – or side effects are excessive, neurologists and neurosurgeons may supplement them with deep brain stimulation. Electrical leads are implanted deep in the brain, and a pulse generator is placed near the collarbone. The device is later programmed with a remote, hand-held controller.
To calm the disorganized muscle contractions of dystonia, doctors generally target a brain structure called the globus pallidus, but studies on precise positioning of electrode contacts and the best programming parameters – such as the intensity and frequency of electrical stimulation – are rare and conflicting. Finding the most effective settings can take months of fine-tuning.
In this retrospective study, investigators examined a database of 94 patients with the most common genetic form of dystonia, DYT1, who had been treated with DBS for at least a year. They selected 21 patients who had good responses to treatment, compiled their demographic and treatment information, and used magnetic resonance imaging scans to create 3-D anatomical models with a fine grid to show exact location of relevant brain structures.
The investigators then simulated the placement of electrodes as they were positioned in the patients’ brains and input the actual stimulation parameters into a computer program – a “volume of tissue activation” model – which calculated detailed information specific to each patient and each electrode. The model draws on principles of neurophysiology – the way nerve cells respond to DBS – the biophysics of voltage distribution from electrodes, and the anatomy of the globus pallidus and surrounding structures.
“We found that clinicians were applying relatively large amounts of energy to wide swaths of the globus pallidus, but the area in common among most individuals was much smaller. We interpret this as being the potential ‘target within the target,’ and if our results are validated in further research and clinical practice, computer modeling may offer a physiologically-based, data-driven, visualized approach to clinical decision-making,” Tagliati said.
(Source: newswise.com)
A new twist on neurological disease: U-M discovery could aid patients with dystonia, Parkinson’s & more
Twist and hold your neck to the left. Now down, and over to the right, until it hurts. Now imagine your neck – or arms or legs – randomly doing that on their own, without you controlling it.
That’s a taste of what children and adults with a neurological condition called dystonia live with every day – uncontrollable twisting and stiffening of neck and limb muscles.
The mystery of why this happens, and what can prevent or treat it, has long puzzled doctors, who have struggled to help their suffering dystonia patients. Now, new research from a University of Michigan Medical School team may finally open the door to answering those questions and developing new options for patients.
In a new paper in the Journal of Clinical Investigation, the researchers describe new strains of mice they’ve developed that almost perfectly mimic a human form of the disease. They also detail new discoveries about the basic biology of dystonia, made from studying the mice.
They’ll soon make the mice available for researchers everywhere to study, to accelerate understanding of all forms of dystonia and the search for better treatments. The lack of such mice has held back research on dystonia for years.
The U-M team’s success in creating a mouse model for the disease came only after 17 years of stubborn, persistent effort – often in the face of setbacks and failure.
Led by U-M neurologist William Dauer, M.D., the team tried to figure out how and why a gene defect leads to an inherited form of dystonia that, intriguingly, doesn’t start until the pre-teen or teen years, after which it progresses for many years but then stops getting worse after the person reaches their mid-20s.
The gene defect responsible, called DYT1, causes brain cells to make a less-active form of a protein called torsinA. But despite more than a decade of effort by Dauer’s team and many others around the world, no one has been able to translate this information into an animal model with dystonia’s characteristic movements.
Using the childhood onset as a clue, Dauer and his team used cutting-edge genetic technology to severely impair torsinA function during early brain development. This novel twist caused the new mice to closely mimic the human disease: they don’t develop dystonia until they reach preteen age in “mouse years,” and their symptoms stop getting worse after a while.
With this powerful tool in hand, Dauer’s team were now able to peer into the brains of these animals to begin to unravel the mysteries of the disease.
In an unexpected development, they found that the lack of torsinA in the brains of dystonic mice led to the death of neurons – a process called neurodegeneration – in just a few highly localized parts of the brain that control movement. Like the dystonic movements, this neurodegeneration began in young mice, progressed for a time, and then became fixed.
“We’ve created a model for understanding why certain parts of the brain are more vulnerable to problems from a certain genetic insult,” says Dauer, an associate professor in the U-M departments of Neurology and Cell & Developmental Biology.
“In this case, we’re showing that in dystonia, the lack of this particular protein during a critical window of time is causing cell death. Every disease is telling us something about biology — one just has to listen carefully.”
(Image caption: The brains of the mice with dystonia (shown in the right column) had much higher levels of neuron death than those without the condition (left column) — and this neurodegeneration was limited to certain areas involved in controlling muscle movements.)
More discoveries to come
Dauer and his team don’t yet know why only one-third of human DYT1 gene mutation carriers develop primary dystonia during their school years, and why those who don’t develop the disease before their early 20s will never go on to develop it.
They believe some critical events during the brain’s development in infancy and childhood may have to do with it - and they’re already working to explore that question in mice.
They also believe their mouse model will help them and other researchers understand how dystonia occurs in people who have Parkinson’s disease, Huntington’s disease, or damage caused by a stroke or brain injury. Some people develop dystonia without either a known gene defect or any of these other diagnoses – a condition called idiopathic dystonia.
In all these cases, as in people with DYT1 mutations, dystonia’s twisting and curling motions likely arise from problems in the area of the brain that controls the body’s motor control system.
In other words, something’s going wrong in the process of sending signals to the nerves that control muscles involved in movement. Studying a “pure” form of dystonia using the mice will allow researchers to understand just what’s going on.
The team’s ultimate goal is to find new treatments for all kinds of dystonia. Currently, children, teens and young adults who develop it can take medications or even opt for a form of neurosurgery called deep brain stimulation. But the drugs carry major side effects and are only partially effective – and brain surgery carries its own risks. Dauer and his team are working to screen drug candidates.
(Source: uofmhealth.org)
Scientists identify new protein in the neurological disorder dystonia, potential for treatments anticipated
A collaborative discovery involving Kansas State University researchers may lead to the first universal treatment for dystonia, a neurological disorder that affects nearly half a million Americans.
Michal Zolkiewski, associate professor of biochemistry and molecular biophysics at Kansas State University, and Jeffrey Brodsky at the University at Pittsburgh co-led a study that focused on a mutated protein associated with early onset torsion dystonia, or EOTD, the most severe type of dystonia that typically affects adolescents before the age of 20. Dystonia causes involuntary and sustained muscle contractions that can lead to paralysis and abnormal postures.
"It’s a painful and debilitating disease for which there is no cure or treatment that would be effective for all patients," Zolkiewski said. "There are some treatments that are being tested, but nothing is really available to those patients that would cure the symptoms completely."
In addition to Zolkiewski and Brodsky, researchers involved in the study included Hui-Chuan Wu, Kansas State University doctoral student in biochemistry and molecular biophysics, Taiwan, and colleagues at the University of Texas Southwestern Medical Center and the University of Adelaide in Australia.
The Journal of Biological Chemistry recently published the team’s study, "The BiP molecular chaperone plays multiple roles during the biogenesis of TorsinA, a AAA+ ATPase associated with the neurological disease Early-Onset Torsion Dystonia." The study was funded by the Dystonia Medical Research Foundation.
Researchers built the study on a decade-old discovery that patients with early onset torsion dystonia typically have a mutated gene that encodes the protein TorsionA.
"TorsinA is a protein that all people have in their bodies," Zolkiewski said. "It appears to perform an important role in the nervous system, but currently nobody knows what that role is. There also is no understanding of the link between the mutation and dystonia."
In order to study protein expression in a living organism, researchers used yeast — one of the simplest living systems. The yeast was engineered to produce the human protein TorsionA.
Observations revealed that a second protein named BiP — pronounced “dip” — helps process the TorsinA protein and maintain its active form. Additionally, researchers found that BiP also guides TorsinA to being destroyed by cells if the protein is defective. Humans carry the BiP protein as well as the TorsinA protein.
"BiP is a molecular chaperone that assists other proteins in maintaining their function," Zolkiewski said. "In this study we found that BiP really has a dual role. On one hand it’s helping TorsinA and on the other it’s leading to its degradation."
Future studies may focus on BiP as a target for treating dystonia, as modulating BiP in human cells would affect TorsinA, Zolkiewski said.
"Because we don’t know what exactly the function of TorsinA is, we may not be able to design a treatment based on that protein," Zolkiewski said. "We know what BiP does, however. It is a pretty well-studied chaperone, which makes it much easier to work with."
(Source: k-state.edu)
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.
Psychogenic diseases, formerly known as ‘hysterical’ illnesses, can have many severe symptoms such as painful cramps or paralysis but without any physical explanation. However, new research from the University of Cambridge and UCL (University College London) suggests that individuals with psychogenic disease, that is to say physical illness that stems from emotional or mental stresses, do have brains that function differently. The research was published today, 25 February, in the journal Brain.
Psychogenic diseases may look very similar to illnesses caused by damage to nerves, the brain or the muscles, or similar to genetic diseases of the nervous system. However, unlike organic diseases, psychogenic diseases do not have any apparent physical cause, making them difficult to diagnose and even more difficult to treat.
“The processes leading to these disorders are poorly understood, complex and highly variable. As a result, treatments are also complex, often lengthy and in many cases there is poor recovery. In order to improve treatment of these disorders, it is important to first understand the underlying mechanism,” said Dr James Rowe from the University of Cambridge.
The study looked at people with either psychogenic or organic dystonia, as well as healthy people with no dystonia. Both types of dystonia caused painful and disabling muscle contractions affecting the leg. The organic patient group had a gene mutation (the DYT1 gene) that caused their dystonia. The psychogenic patients had the symptoms of dystonia but did not have any physical explanation for the disease, even after extensive investigations.
The scientists performed PET brain scans on the volunteers at UCL, to measure the blood flow and brain activity of both of the groups, and healthy volunteers. The participants were scanned with three different foot positions: resting, moving their foot, and holding their leg in a dystonic position. The electrical activity of the leg muscles was measured at the same time to determine which muscles were engaged during the scans.
The researchers found that the brain function of individuals with the psychogenic illness was not normal. The changes were, however, very different from the brains of individuals with the organic (genetic) disease.
Dr Anette Schrag, from UCL, said: “Finding abnormalities of brain function that are very different from those in the organic form of dystonia opens up a way for researchers to learn how psychological factors can, by changing brain function, lead to physical problems.”
Dr Rowe added: “What struck me was just how very different the abnormal brain function was in patients with the genetic and the psychogenic dystonia. Even more striking was that the differences were there all the time, whether the patients were resting or trying to move.”
Additionally, the researchers found that one part of the brain previously thought to indicate psychogenic disease is unreliable: abnormal activity of the prefrontal cortex was thought to be the hallmark of psychogenic diseases. In this study, the scientists showed that this abnormality is not unique to psychogenic disease, since activity was also present in the patients with the genetic cause of dystonia when they tried to move their foot.
Dr Arpan Mehta, from the University of Cambridge, said: “It is interesting that, despite the differences, both types of patient had one thing in common - a problem at the front of the brain. This area controls attention to our movements and although the abnormality is not unique to psychogenic dystonia, it is part of the problem.”
This type of illness is very common. Dr Schrag said: “One in six patients that see a neurologist has a psychogenic illness. They are as ill as someone with organic disease, but with a different cause and different treatment needs. Understanding these disorders, diagnosing them early and finding the right treatment are all clearly very important. We are hopeful that these results might help doctors and patients understand the mechanism leading to this disorder, and guide better treatments.”
In Some Dystonia Cases, Deep Brain Therapy Benefits May Linger After Device Turned Off
Two patients freed from severe to disabling effects of dystonia through deep brain stimulation therapy continued to have symptom relief for months after their devices accidentally were fully or partly turned off, according to a report published online Feb. 11 in the journal Movement Disorders.
“Current thought is that symptoms will worsen within hours or days of device shut-off, but these two young men continued to have clinical benefit despite interruption of DBS therapy for several months. To our knowledge, these two cases represent the longest duration of retained benefit in primary generalized dystonia. Moreover, when these patients’ symptoms did return, severity was far milder than it was before DBS,” said senior author Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai’s Department of Neurology.
Dystonia causes muscles to contract, with the affected body part twisting involuntarily and symptoms ranging 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 then programmed with a remote, hand-held controller. Tagliati is an expert in device programming, which fine-tunes stimulation for individual patients.
Few studies have looked at the consequences of interrupted DBS therapy, although one found “fairly rapid worsening of dystonia in 14 patients after interruption of stimulation for 48 hours, with symptom severity at times becoming worse than the pre-operative baseline.” In another study of 10 patients with generalized dystonia, however, symptoms did not return in four patients when stimulation was discontinued for 48 hours.
Findings from the 10-patient study correlate well with these two cases, Tagliati said.
“It appears that several factors – age, duration of disease, length of time the patient has received DBS treatment and stimulation parameters – determine which patients may retain symptom relief after prolonged DBS interruption. Our two patients were young, 20 years old. They both began DBS therapy a relatively short time after disease onset; one at four years and the other at seven years. One had received continuous stimulation for five years and the other for 18 months before stimulation was interrupted,” Tagliati said.
“We can’t say for certain why these factors make the difference,” he added, “But we theorize that a younger brain with shorter exposure to the negative effects of dystonia may be more responsive to therapy and have greater ‘plasticity’ to adapt back to normal. Both of our patients received DBS therapy at a lower energy than most patients experience, suggesting the possibility that low-frequency stimulation over an extended time may help retrain the brain’s low-frequency electrical activity.”
Both instances of device shut-off were accidental and were discovered during doctor visits after mild symptoms returned. The patient who had undergone five years of DBS therapy had only one stimulator turned off for about three months; the one stimulating the left side of his brain remained active. In the other patient, the left device had been off for about seven months and the right one for two months, Tagliati said.
Tagliati was senior author of a 2011 Journal of Neurology article on a study showing that for patients suffering from dystonia, deep brain therapy tends to get better, quicker results when started earlier rather than later.
“We knew from earlier work that younger patients with shorter disease duration had better clinical outcomes in the short term. In our 2011 article, we reported that they fare best in the long term, as well. That study uniquely showed that age and disease duration play complementary roles in predicting long-term clinical outcomes. The good news for older patients is that while they may not see the rapid gains of younger patients, their symptoms may gradually improve over several years,” Tagliati said.