Filling me softly

Surgical implants are widely used in modern medicine but their effectiveness is often compromised by how our bodies react to them. Now, scientists at the University of Cambridge have discovered that implant stiffness is a major cause of this so-called foreign body reaction.

This is the first time that stiffness of implant materials has been shown to be involved in foreign body reactions. The findings – published in the journal Biomaterials – could lead to major improvements in surgical implants and the quality of life of patients whose lives depend on them.

Foreign bodies often trigger a process that begins with inflammation and ends with the foreign body being encapsulated with scar tissue. When this happens after an accident or injury, the process is usually vital to healing, but when the same occurs around, for example, electrodes implanted in the brain to alleviate tremor in Parkinson’s disease, it may be problematic.

Despite decades of research, the process remains poorly understood as neither the materials from which these implants are made, nor their electrical properties, can explain what triggers inflammation.

Instead of looking for classical biological causes, a group of Cambridge physicists, engineers, chemists, clinical scientists and biologists decided to take a different tack and examine the impact of an implant’s stiffness on the inflammatory process.

According to Dr Kristian Franze, one of the authors of the study: “Electrodes that are implanted in the brain, for example, should be chemically inert, and these foreign body reactions occur whether or not these electrodes are switched on, so it’s not the electrical signalling.

“We thought that an obvious difference between electrodes and brain tissue is stiffness. Brain tissue is as soft as cream cheese, it is one of the softest tissues in the body, and electrodes are orders of magnitude stiffer.”

To test their hypothesis that mechanical signals trigger inflammation, the team cultured brain cells on two different substrates. The substrates were chemically identical but one was as soft as brain tissue and the other two orders of magnitude stiffer, akin to the stiffness of muscle tissue.

When they examined the cells, they found major differences in their shape. “The cells grown on the stiffer substrate were very flat, whereas those grown on the soft substrate looked much more like cells you find in the brain,” he explained.

To confirm the findings they did genetic and other tests, which revealed that many of the inflammatory genes and proteins known to be involved in foreign body reactions had been upregulated on stiff surfaces.

The team then implanted a tiny foreign body into rats’ brains. The implant was made of a single material but one side was as soft as brain tissue and the other as stiff as muscle. They found much greater foreign body reaction around the stiff part of the implant.

“This strongly indicates that stiffness of a material may trigger foreign body reactions. It does not mean there aren’t other triggers, but stiffness definitely contributes and this is something new that hasn’t been known before,” he said.

The findings could have major implications for the design of implants used in the brain and other parts of the body.

“While it may eventually be possible to make implants out of new, much softer materials, our results suggest that in the short term, simply coating existing implants with materials that match the stiffness of the tissue they are being implanted into will help reduce foreign body reactions,” said Dr Franze.

A shock to the system: Electroconvulsive Therapy shows mood disorder-specific therapeutic benefits

The oldest well-established procedure for somatic treatment of unipolar and bipolar disorders, electroconvulsive therapy (ECT) has, at best, a variegated reputation – and not just in its reputation for being a “barbaric” treatment modality (which, as it turns out, it is not). The scientific, clinical, and ethical controversy extends to unanswered questions about its precise mechanism of action – that is, how major electrical discharge over half the brain shows efficacy in recovery from a range of sometimes quite distinct psychological and psychiatric disorders. Recently, however, scientists at Université de Lausanne, Lausanne, Switzerland and Charité University Medicine, Berlin, Germany found local but not general anatomical brain changes following electroconvulsive therapy that are differently distributed in each disease, and are actually the areas believed to be abnormal in each disorder. Since interaction between ECT and specific pathology appears to be therapeutically causal, the researchers state that their results have implications for deep brain stimulation, transcranial magnetic stimulation and other electrically-based brain treatments.

Prof. Bogdan Draganski discussed the paper that he, Dr. Juergen Dukart and their co-authors published in Proceedings of the National Academy of Sciences.

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The Cyborgs Era Has Started

Medical implants, complex interfaces between brain and machine or remotely controlled insects: Recent developments combining machines and organisms have great potentials, but also give rise to major ethical concerns. In their review entitled “Chemie der Cyborgs – zur Verknüpfung technischer Systeme mit Lebewesen” (The Chemistry of Cyborgs – Interfacing Technical Devices with Organisms), KIT scientists discuss the state of the art of research, opportunities, and risks. The review is published now by the renowned journal “Angewandte Chemie Int. Ed.”

They are known from science fiction novels and films – technically modified organisms with extraordinary skills, so-called cyborgs. This name originates from the English term “cybernetic organism”. In fact, cyborgs that combine technical systems with living organisms are already reality. The KIT researchers Professor Christof M. Niemeyer and Dr. Stefan Giselbrecht of the Institute for Biological Interfaces 1 (IBG 1) and Dr. Bastian E. Rapp, Institute of Microstructure Technology (IMT), point out that this especially applies to medical implants.

In recent years, medical implants based on smart materials that automatically react to changing conditions, computer-supported design and fabrication based on magnetic resonance tomography datasets or surface modifications for improved tissue integration allowed major progress to be achieved. For successful tissue integration and the prevention of inflammation reactions, special surface coatings were developed also by the KIT under e.g. the multidisciplinary Helmholtz program “BioInterfaces”.

Progress in microelectronics and semiconductor technology has been the basis of electronic implants controlling, restoring or improving the functions of the human body, such as cardiac pacemakers, retina implants, hearing implants, or implants for deep brain stimulation in pain or Parkinson therapies. Currently, bioelectronic developments are being combined with robotics systems to design highly complex neuroprostheses. Scientists are working on brain-machine interfaces (BMI) for the direct physical contacting of the brain. BMI are used among others to control prostheses and complex movements, such as gripping. Moreover, they are important tools in neurosciences, as they provide insight into the functioning of the brain. Apart from electric signals, substances released by implanted micro- and nanofluidic systems in a spatially or temporarily controlled manner can be used for communication between technical devices and organisms.

BMI are often considered data suppliers. However, they can also be used to feed signals into the brain, which is a highly controversial issue from the ethical point of view. “Implanted BMI that feed signals into nerves, muscles or directly into the brain are already used on a routine basis, e.g. in cardiac pacemakers or implants for deep brain stimulation,” Professor Christof M. Niemeyer, KIT, explains. “But these signals are neither planned to be used nor suited to control the entire organism – brains of most living organisms are far too complex.”

Brains of lower organisms, such as insects, are less complex. As soon as a signal is coupled in, a certain movement program, such as running or flying, is started. So-called biobots, i.e. large insects with implanted electronic and microfluidic control units, are used in a new generation of tools, such as small flying objects for monitoring and rescue missions. In addition, they are applied as model systems in neurosciences in order to understand basic relationships.

Electrically active medical implants that are used for longer terms depend on reliable power supply. Presently, scientists are working on methods to use the patient body’s own thermal, kinetic, electric or chemical energy.

In their review the KIT researchers sum up that developments combining technical devices with organisms have a fascinating potential. They may considerably improve the quality of life of many people in the medical sector in particular. However, ethical and social aspects always have to be taken into account.

Disparities Run Deep: Parkinson’s Patients Utilization of Deep Brain Stimulation Treatment Reduced within Demographic Groups

Among Parkinson’s disease (PD) patients, female, black, and Asian patients are substantially less likely to receive proven deep brain stimulation (DBS) surgery to improve tremors and motor symptoms, according to a new report by a Perelman School of Medicine at the University of Pennsylvania researcher who identified considerable disparities among Medicare recipients receiving DBS for Parkinson’s disease. The study, published in Neurology, found that patients from neighborhoods of lower socioeconomic status were less likely to receive DBS, regardless of race or sex. And patients of minority-serving physician practices were also less likely to receive DBS, irrespective of race. The study demonstrates a need to adjust policy and incentives to provide state of the art care for all Parkinson’s patients.

Parkinson’s disease, a progressive neurodegenerative disease, affects more than 2 million Americans and cannot be prevented or halted. DBS is often prescribed for PD patients when pharmacologic treatments are unable to control involuntary movements or decrease effectiveness over time. While DBS is effective, it requires extensive pre-operative testing, is contraindicated for PD patients who have evidence of cognitive impairment or dementia, and includes out-of-pocket costs that may not be covered by Medicare. DBS out-of-pocket costs average around $2,200 (2007 dollars) per year — 41 percent more than annual non-DBS costs —and would consume approximately 7 percent of the average income in the lowest socioeconomic quartile, potentially limiting the willingness of low-income seniors to consider DBS.

"There are widespread disparities among Parkinson’s patients that are restricting equal utilization of evidence-based care, limiting patients’ quality of life, and increasing societal and health care costs," said lead study author Allison Willis, MD, Assistant Professor of Neurology and of Epidemiology at Penn Medicine. Dr. Willis collaborated on the study with colleagues from Washington University School of Medicine in St. Louis. "Efforts to overcome these disparities, through policy or reimbursement changes, can benefit elders and socioeconomically disadvantaged patients with Parkinson’s disease, as well as other vulnerable groups," said Willis.

Analyzing more than 665,000 Medicare beneficiaries with a Parkinson’s diagnosis between 2007 and 2009 - a decade after DBS was approved for Parkinson’s disease patients - the team identified 8,420 patients  treated with DBS (approximately 1 percent). Nearly 95 percent of DBS recipients were white, and 59 percent were male. Hispanic PD patients were nearly equally represented among DBS (2.2 percent of all cases) and non-DBS cases (1.7 percent), whereas black and Asian populations were significantly underrepresented among DBS cases. Black PD patients accounted for 1 percent of DBS cases, and 5.5 percent of non-DBS cases, while less than 1 percent of Asian PD patients received DBS, compared to 1.5 who did not. Women of all races accounted for 41 percent of DBS cases, but 50 percent of non-DBS cases.

Patients with PD of all races who were treated by physicians with the highest concentrations of minority (Asian, Hispanic or black) patients had at least a 15 percent lower likelihood of receiving DBS, compared to providers caring for a small percentage of minority patients. While the data may not account for those who were offered DBS and refused or who were evaluated and did not qualify for DBS, the study suggests that minority-serving providers may be unlikely to perform or refer any of their Medicare beneficiaries with PD for DBS.

In addition, early data suggest that socioeconomic challenges to patients with fixed incomes may also contribute to the treatment disparities. Further research is needed to compare DBS out-of-pocket costs with standard medical and surgical procedures for other conditions.

Penn researchers will continue to study clinical characteristics and progression of disease in minorities and women, to see if they may account for any of the DBS utilization differences. In addition, they hope to look further into physician and practice characteristics along with local medical resources to determine how care differences contribute to disparities in individual DBS use.

Stimulating brain cells stops binge drinking, animal study finds

Researchers at the University at Buffalo have found a way to change alcohol drinking behavior in rodents, using the emerging technique of optogenetics, which uses light to stimulate neurons.

Their work could lead to powerful new ways to treat alcoholism, other addictions, and neurological and mental illnesses; it also helps explain the underlying neurochemical basis of drug addiction.

The findings, published in November in Frontiers in Neuroscience, are the first to demonstrate a causal relationship between the release of dopamine in the brain and drinking behaviors of animals. Research like this, which makes it possible to map the neuronal circuits responsible for specific behaviors, is a major focus of President Obama’s Brain Research for Advancing Innovative Neurotechnologies initiative, known as BRAIN.

In the experiments, rats were trained to drink alcohol in a way that mimics human binge-drinking behavior.

First author Caroline E. Bass, PhD, assistant professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences explains:  “By stimulating certain dopamine neurons in a precise pattern, resulting in low but prolonged levels of dopamine release, we could prevent the rats from binging. The rats just flat out stopped drinking,” she says.

Bass’s co-authors are at Wake Forest University, where she worked previously.

Interestingly, the rodents continued to avoid alcohol even after the stimulation of neurons ended, she adds.

“For decades, we have observed that particular brain regions light up or become more active in an alcoholic when he or she drinks or looks at pictures of people drinking, for example, but we didn’t know if those changes in brain activity actually governed the alcoholic’s behavior,” says Bass.

The researchers activated the dopamine neurons through a type of deep brain stimulation, but unlike techniques now used to treat certain neurological disorders, such as severe tremors in Parkinson’s disease patients, this new technique, called optogenetics, uses light instead of electricity to stimulate neurons.

“Electrical stimulation doesn’t discriminate,” Bass explains. “It hits all the neurons, but the brain has many different kinds of neurons, with different neurotransmitters and different functions. Optogenetics allows you to stimulate only one type of neuron at a time.”

Bass specializes in using viral vectors to study the brain in substance abuse. In this study, she used a virus to introduce a gene encoding a light-responsive protein into the animals’ brains. That protein then activated a specific subpopulation of dopamine neurons in the brain’s reward system.

“I created a virus that will make this protein only in dopaminergic neurons,” Bass says.

The neuronal pathways affected in this research are involved in many neurological disorders, she says. For that reason, the results have application not only in understanding and treating alcohol-drinking behaviors in humans, but also in many devastating mental illnesses and neurological diseases that have a dopamine component.

Bass notes that this ability to target genes to dopamine neurons could potentially lead to the use of gene therapy in the brain to mitigate many of these disorders.

“We can target dopamine neurons in a part of the brain called the nigrostriatal pathway, which is what degenerates in Parkinson’s disease,” she says. “If we could infuse a viral vector into that part of the brain, we could target potentially therapeutic genes to the dopamine neurons involved in Parkinson’s. And by infusing the virus into other areas of the brain, we could potentially deliver therapeutic genes to treat other neurological diseases and mental illnesses, including schizophrenia and depression.”

Researchers Study Alcohol Addiction Using Optogenetics

Wake Forest Baptist Medical Center researchers are gaining a better understanding of the neurochemical basis of addiction with a new technology called optogenetics.

In neuroscience research, optogenetics is a newly developed technology that allows researchers to control the activity of specific populations of brain cells, or neurons, using light. And it’s all thanks to understanding how tiny green algae, that give pond scum its distinctive color, detect and use light to grow.

The technology enables researchers like Evgeny A. Budygin, Ph.D., assistant professor of neurobiology and anatomy at Wake Forest Baptist, to address critical questions regarding the role of dopamine in alcohol drinking-related behaviors, using a rodent model.

"With this technique, we’ve basically taken control of specific populations of dopamine cells, using light to make them respond - almost like flipping a light switch," said Budygin. "These data provide us with concrete direction about what kind of patterns of dopamine cell activation might be most effective to target alcohol drinking."

The latest study from Budygin and his team published online in last month’s journal Frontiers in Behavioral Neuroscience. Co-author Jeffrey L. Weiner, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist, said one of the biggest challenges in neuroscience has been to control the activity of brain cells in the same way that the brain actually controls them. With optogenetics, neuroscientists can turn specific neurons on or off at will, proving that those neurons actually govern specific behaviors.

"We have known for many years what areas of the brain are involved in the development of addiction and which neurotransmitters are essential for this process," Weiner said. "We need to know the causal relationship between neurochemical changes in the brain and addictive behaviors, and optogenetics is making that possible now."

The researchers used cutting-edge molecular techniques to express the light-responsive channelrhodopsin protein in a specific population of dopamine cells in the brain-reward system of rodents. They then implanted tiny optical fibers into this brain region and were able to control the activity of these dopamine cells by flashing a blue laser on them.

"You can place an electrode in the brain and apply an electrical current to mimic the way brain cells get excited, but when you do that you’re activating all the cells in that area," Weiner said. "With optogenetics, we were able to selectively control a specific population of dopamine cells in a part of the brain-reward system. Using this technique, we discovered distinct patterns of dopamine cell activation that seemed to be able to disrupt the alcohol-drinking behavior of the rats."

Weiner said there is translational value from the study because “it gives us better insight into how we might want to use something like deep-brain stimulation to treat alcoholism. Doctors are starting to use deep-brain stimulation to treat everything from anxiety to depression, and while it works, there is little scientific understanding behind it, he said.

Budygin agreed and said this kind of project wouldn’t be possible without cross campus collaboration between neurobiology and anatomy, physiology and pharmacology and physics. “Now we are taking the first steps in this direction,” he said. “It was impossible before the optogenetic era.”

Clinical Trial Brings Positive Results for Tinnitus Sufferers

UT Dallas researchers have demonstrated that treating tinnitus, or ringing in the ears, using vagus nerve stimulation-tone therapy is safe and brought significant improvement to some of the participants in a small clinical trial.

Drs. Sven Vanneste and Michael Kilgard of the School of Behavioral and Brain Sciences used a new method pairing vagus nerve stimulation (VNS) with auditory tones to alleviate the symptoms of chronic tinnitus. Their results were published on Nov. 20 in the journal Neuromodulation: Technology at the Neural Interface.

VNS is an FDA-approved method for treating various illnesses, including depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which relays information about the state of the body to the brain.

“The primary goal of the study was to evaluate safety of VNS-tone therapy in tinnitus patients,” Vanneste said. “VNS-tone therapy was expected to be safe because it requires less than 1 percent of the VNS approved by the FDA for the treatment of intractable epilepsy and depression. There were no significant adverse events in our study.”

According to Vanneste, more than 12 million Americans have tinnitus severe enough to seek medical attention, of which 2 million are so disabled that they cannot function normally. He said there has been no consistently effective treatment.

The study, which took place in Antwerp, Belgium, involved implanting 10 tinnitus sufferers with a stimulation electrode directly on the vagus nerve. They received 2 ½ hours of daily treatment for 20 days. The participants had lived with tinnitus for at least a year prior to participating in the study, and showed no benefit from previous audiological, drug or neuromodulation treatments. Electrical pulses were generated from an external device for this study, but future work could involve using internal generators, eliminating the need for clinical visits.

Half of the participants demonstrated large decreases in their tinnitus symptoms, with three of them showing a 44-percent reduction in the impact of tinnitus on their daily lives. Four people demonstrated clinically meaningful reductions in the perceived loudness of their tinnitus by 26 decibels.

Five participants, all of whom were on medications for other problems, did not show significant changes. However, the four participants who benefited from the therapy were not using any medications. The report attributes drug interactions as blocking the effects of the VNS-tone therapy.

“In all, four of the 10 patients showed relevant decreases on tinnitus questionnaires and audiological measures,” Vanneste said. “The observation that these improvements were stable for more than two months after the end of the one month therapy is encouraging.”

Power of precision medicine in successful treatment of patient with disabling OCD

A multidisciplinary team led by a geneticist and psychiatrist from Cold Spring Harbor Laboratory’s (CSHL) Stanley Institute for Cognitive Genomics today publish a paper providing a glimpse of both the tremendous power and the current limitations of what is sometimes called “precision medicine.”

Precision medicine is an approach to diagnosis and treatment that tailors therapeutic care to individuals in a highly specific manner, and which brings to bear powerful new technologies that have not yet made it into the mainstream of clinical medicine, in part because they remain unproven.

Gholson J. Lyon, M.D., Ph.D., a CSHL researcher in molecular genetics and also a practicing psychiatrist, and collaborators at the University of Utah, the Utah Foundation for Biomedical Research (UFBR) and the companies Omicia, Inc. and AssureRx, report on their recruitment and treatment of a single patient with severe psychiatric illness. The man, identified as a 37-year-old U.S. military veteran, suffered from a form of obsessive-compulsive disorder (OCD) that rendered him completely disabled – profoundly compulsive and anxious, occasionally paranoid, and unable to hold a job or form meaningful relationships.

Over the past three years, the team successfully treated the man with an experimental form of electrical brain stimulation, called deep-brain stimulation (DBS). To date, DBS has been used most frequently to lessen symptoms in people with advanced Parkinson’s disease and also on an experimental basis to help lift otherwise untreatable, severe  depression. Worldwide, only around 100 other people with OCD have been reported to have received DBS treatment on a trial basis. This was the first such instance, however, in which an individual with such severe mental illness, being treated with DBS, also consented to and received whole-genome sequencing, and rigorous post-sequencing analysis of the results, accompanied by genetic counseling. 

Integrating the results

Each phase of the study generated significant data; but never had such data been integrated in the context of a single clinical psychiatric case. The results, which appear online today in the journal PeerJ, show that the patient was greatly helped by DBS. Over the treatment period, symptoms associated with OCD diminished to the point that the individual was able to “regain a quality of life that he had not previously experienced in over 15 years,” Dr. Lyon and colleagues report. As the electrical stimulation of his brain via DBS was optimized over time (this involved gradually increasing the voltage used in electrical stimulation), he was able to participate in regular exercise, work as a volunteer, and eventually meet someone and get married. 

The researchers noted that several times during the treatment, when power from the battery that drives the DBS signals was either drained or not activated by the patient, symptoms of severe OCD returned over the course of 12-24 hours and rapidly became debilitating. This was both a powerful lesson to the patient to keep the device charged (the battery is rechargeable) and vivid evidence to the scientists regarding the device’s role in producing the patient’s observed symptomatic improvements.  

Whole-genome sequencing, meantime, revealed that the patient carries at least three gene variants, or alleles, that have been associated in other studies with neuropsychiatric illness. These variants were in genes that encode proteins called BDNF, MTHFR and ChAT. The BDNF gene variant is of particular interest. Its protein is a prime growth factor essential in the early development and subsequent healthy function of the brain and nervous system. The other two variants have also been associated in past studies with possibly increasing the risks of mental illness. 

Other gene variants were found that have implications for the way the patient is either able or unable to metabolize particular kinds of drugs.  These and literally thousands of other bits of personal genomic information had no immediate impact on his treatment or prognosis, but were archived by Dr. Lyon’s team in the hope that at some later date they might be useful. One of the gene variants did prompt a referral for an eye exam, which revealed bilateral cataracts and poor night vision in this person, which the investigators are currently following up.

“Although we believe in archiving and managing all genetic results and not just a small subset of presently-known ‘risk genes,’ we did analyze the 57 genes in our subject’s genome that are currently recommended for ‘return of results’ to patients by the American College of Medical Genetics,” Dr. Lyon and the team notes. 

“I met with this individual to go over the results with him” Dr. Lyon adds, “along with adding some of the findings into his paper-based medical record. We also contacted physicians and other officials at the US Veterans Administration office to offer to incorporate these data into the VA electronic medical record for this patient. We were told, however, that there is no current capacity at the VA to incorporate any genomic variant data.”

The inability even to enter the data in existing electronic health record databases points to the practical problems that remain in using comprehensive data sets to help evaluate and treat patients in a clinical context.  

The team, however, believes its results demonstrate that “one can learn a substantial amount from detailed study of particular individuals,” and argues that “we are entering an era of precision medicine in which we can learn from and collect substantial data on informative individual cases.” They further note: “The genomic data we gathered would have been more helpful if obtained much earlier in the patient’s medical course, as it could have provided guidance on which medications to avoid or to provide in increased doses.”