Patients aged between 50 to 70 years with a mechanical heart valve replacement had better long-term survival compared to those with a biological valve, new research led by the University of Bristol has found. The study is published in the European Journal of Cardio-Thoracic Surgery.
The last two decades have seen an increase in the use of biological over mechanical heart valve replacements. However, while short-term clinical outcomes are known to be the same, long-term outcomes are still under debate.
Existing guidelines support the use of mechanical valves made of synthetic materials in patients below the age of 50, while biological valves made of animal tissue are favoured for those above the age of 65 or 70. The guidelines leave the choice to the decision of surgeons and patients who are 50 to 70 years old.
The research team wanted to find out the clinical outcomes for patients aged between 50 to 70 years undergoing elective and urgent heart valve replacement at the Bristol Heart Institute (BHI) over a 27 year period [1996 to 2023].
The researchers also sought to investigate trends, early outcomes and long-term survival rates, the incidence of repeat valve interventions and patient prosthesis mismatch (PPM).
A total of 1708 (61% male) patients with an average age of 63 years were included with 1191 (69.7%) receiving a biological valve replacement.
The research found there were no short-term differences when comparing patients receiving biological and mechanical valves. However, patients who received mechanical valves had better long-term survival up to 13 years after having surgery.
Patients with a size 19mm biological valve replacement (a fairly small valve commonly used in females) had the worse long-term survival. Patients with a size 21mm mechanical valve had better survival compared to both size 19 and 21mm biological valves. The study confirmed that severe PPM is a significant risk factor for poor long-term survival.
Gianni Angelini, BHF Professor of Cardiac Surgery at the Bristol Medical School: Translational Health Sciences (THS), Director of the Bristol Heart Institute and corresponding author, said: “Our study has implications for decision-making in surgical heart valve replacements for patients aged between 50 and 70 years old. The evidence supporting better long-term survival in patients receiving a mechanical heart valve suggests the current trend favouring biological valves in this age bracket should be urgently reconsidered. The survival benefit is especially clear in smaller sized valves.”
The research team recommends the evaluation of the long-term benefits associated with mechanical valves, especially in smaller sizes, despite long-term blood thinners not being needed with biological valves.
Study limitations
The single-institution design, retrospective collection of data, and absence of randomisation make the study open to bias. The lack of echocardiographic information could potentially underestimate the incidence of structural valve failure. In terms of repeat valve interventions, only patients who underwent re-do surgical aortic valve replacement or valve in valve transcatheter aortic valve implantation (TAVI) at the BHI were included.
As the BHI is a supra-regional centre, it is very unlikely that many patients might have undergone reintervention in other institutions. The cause of death (cardiovascular/non cardiovascular) was not available.
In a paper recently published in The Lancet Digital Health, a scientific team led by Stanisa Raspopovic from MedUni Vienna looks at the progress and challenges in the research and development of brain implants. New achievements in the field of this technology are seen as a source of hope for many patients with neurological disorders and have been making headlines recently. As neural implants have an effect not only on a physical but also on a psychological level, researchers are calling for particular ethical and scientific care when conducting clinical trials.
The research and development of neuroprostheses has entered a phase in which experiments on animal models are being followed by tests on humans. Only recently, reports of a paraplegic patient in the USA who was implanted with a brain chip as part of a clinical trial caused a stir. With the help of the implant, the man can control his wheelchair, operate the keyboard on his computer and use the cursor in such a way that he can even play chess. About a month after the implantation, however, the patient realised that the precision of the cursor control was decreasing and the time between his thoughts and the computer actions was delayed.
“The problem could be partially, but not completely, resolved – and illustrates just one of the potential challenges for research into this technology,” explains study author Stanisa Raspopovic from MedUni Vienna’s Center for Medical Physics and Biomedical Engineering, who published the paper together with Marcello Ienca (Technical University of Munich) and Giacomo Valle (ETH Zurich). “The questions of who will take care of the technical maintenance after the end of the study and whether the device will still be available to the patient at all after the study has been cancelled or completed are among the many aspects that need to be clarified in advance in neuroprosthesis research and development, which is predominantly industry-led.”
Protection of highly sensitive data
Neuroprostheses establish a direct connection between the nervous system and external devices and are considered a promising approach in the treatment of neurological impairments such as paraplegia, chronic pain, Parkinson’s disease and epilepsy. The implants can restore mobility, alleviate pain or improve sensory functions. However, as they form an interface to the human nervous system, they also have an effect on a psychological level: “They can influence consciousness, cognition and affective states and even free will. This means that conventional approaches to safety and efficacy assessment, such as those used in clinical drug trials, are not suitable for researching these complex systems. New models are needed to comprehensively evaluate the subjective patient experience and protect the psychological privacy of the test subjects,” Raspopovic points out.
The special technological features of neuroimplants, in particular the ability to collect and process neuronal data, pose further challenges for clinical validation and ethical oversight. Neural data is considered particularly sensitive and requires an even higher level of protection than other health information. Unsecured data transmission, inadequate data protection guidelines and the risk of hacker attacks are just some of the potential vulnerabilities that require special precautions in this context. “The use of neural implants cannot be reduced to medical risks,” summarises Stanisa Raspopovic. “We are only in the initial phase of clinical studies on these technological innovations. But questions of ethical and scientific diligence in dealing with this highly sensitive topic should be clarified now and not only after problems have arisen in test subjects or patients.”
A brain-computer interface, surgically placed in a research participant with tetraplegia, paralysis in all four limbs, provided an unprecedented level of control over a virtual quadcopter – just by thinking about moving his unresponsive fingers.
The technology divides the hand into three parts: the thumb and two pairs of fingers (index and middle, ring and small). Each part can move both vertically and horizontally. As the participant thinks about moving the three groups, at times simultaneously, the virtual quadcopter responds, manoeuvring through a virtual obstacle course.
It’s an exciting next step in providing those with paralysis the chance to enjoy games with friends while also demonstrating the potential for performing remote work.
“This is a greater degree of functionality than anything previously based on finger movements,” said Matthew Willsey, U-M assistant professor of neurosurgery and biomedical engineering, and first author of a new research paper in Nature Medicine. The testing that produced the paper was conducted while Willsey was a researcher at Stanford University, where most of his collaborators are located.
While there are noninvasive approaches to allow enhanced video gaming such as using electroencephalography to take signals from the surface of the user’s head, EEG signals combine contributions from large regions of the brain. The authors believe that to restore highly functional fine motor control, electrodes need to be placed closer to the neurons. The study notes a sixfold improvement in the user’s quadcopter flight performance by reading signals directly from motor neurons vs. EEG.
To prepare the interface, patients undergo a surgical procedure in which electrodes are placed in the brain’s motor cortex. The electrodes are wired to a pedestal that is anchored to the skull and exits the skin, which allows a connection to a computer.
“It takes the signals created in the motor cortex that occur simply when the participant tries to move their fingers and uses an artificial neural network to interpret what the intentions are to control virtual fingers in the simulation,” Willsey said. “Then we send a signal to control a virtual quadcopter.”
A screenshot of the game display shows the quadcopter following a green path around the rings. The inset shows a hand avatar. The neural implant records from nearby neurons and algorithms determine the intended movements for the hand avatar. The finger positions are then used to control the virtual quadcopter. Image credit: Nature Medicine
The research, conducted as part of the BrainGate2 clinical trials, focused on how these neural signals could be coupled with machine learning to provide new options for external device control for people with neurological injuries or disease. The participant first began working with the research team at Stanford in 2016, several years after a spinal cord injury left him unable to use his arms or legs. He was interested in contributing to the work and had a particular interest in flying.
“The quadcopter simulation was not an arbitrary choice, the research participant had a passion for flying,” said Donald Avansino, co-author and computer scientist at Stanford University. “While also fulfilling the participant’s desire for flight, the platform also showcased the control of multiple fingers.”
Co-author Nishal Shah, incoming professor of electrical and computer engineering at Rice University, explained, “controlling fingers is a stepping stone; the ultimate goal is whole body movement restoration.”
Jaimie Henderson, a Stanford professor of neurosurgery and co-author of the study, said the work’s importance goes beyond games. It allows for human connection.
“People tend to focus on restoration of the sorts of functions that are basic necessities – eating, dressing, mobility – and those are all important,” he said. “But oftentimes, other equally important aspects of life get short shrift, like recreation or connection with peers. People want to play games and interact with their friends.”
A person who can connect with a computer and manipulate a virtual vehicle simply by thinking, he says, could eventually be capable of much more.
“Being able to move multiple virtual fingers with brain control, you can have multifactor control schemes for all kinds of things,” Henderson said. “That could mean anything, from operating CAD software to composing music.”
The researchers’ experiments showed that the catheter electrodes could be successfully delivered and guided into the ventricular spaces and brain surface for electrical stimulation. Image courtesy of Rice University.
A team of researchers has developed a technique for diagnosing, managing and treating neurological disorders with minimal surgical risks. The team’s findings were published in Nature Biomedical Engineering.
While traditional approaches for interfacing with the nervous system often require creating a hole in the skull to interface with the brain, the researchers have developed an innovative method known as endocisternal interfaces (ECI), allowing for electrical recording and stimulation of neural structures, including the brain and spinal cord, through cerebral spinal fluid (CSF).
“Using ECI, we can access multiple brain and spinal cord structures simultaneously without ever opening up the skull, reducing the risk of complications associated with traditional surgical techniques,” said study leader Robinson Jacob Robinson, professor of electrical and computer engineering and bioengineering at Rice University.
ECI uses CSF, which surrounds the nervous system, as a pathway to deliver targeted devices. By performing a simple lumbar puncture in the lower back, researchers can navigate a flexible catheter to access the brain and spinal cord.
Using miniature magnetoelectric-powered bioelectronics, the entire wireless system can be deployed through a small percutaneous procedure. The flexible catheter electrodes can be navigated freely from the spinal subarachnoid space to the brain ventricles.
“This is the first reported technique that enables a neural interface to simultaneously access the brain and spinal cord through a simple and minimally invasive lumbar puncture,” said University of Texas Medical Branch’s Peter Kan, professor and Chair of Neurosurgery, who also led the study. “It introduces new possibilities for therapies in stroke rehabilitation, epilepsy monitoring and other neurological applications.”
To test the hypothesis, the research team characterised the endocisternal space and measured the width of the subarachnoid, or fluid-filled space, in human patients using MRI. The researchers then conducted experiments in large animal models, specifically sheep, to validate the feasibility of the new neural interface.
Their experiments showed that the catheter electrodes could be successfully delivered and guided into the ventricular spaces and brain surface for electrical stimulation. By using the magnetoelectric implant, the researchers were able to record electrophysiologic signals such as muscle activation and spinal cord potentials.
Preliminary safety results showed that the ECI remained functional with minimal damage up to 30 days after the electronic device was implanted chronically into the brain.
Moreover, the study revealed that unlike endovascular neural interfaces that require antithrombotic medication and are limited by the small size and location of blood vessels, ECI offers broader access to neural targets without the medication.
“This technology creates a new paradigm for minimally invasive neural interfaces and could lower the risk of implantable neurotechnologies, enabling access to wider patient populations,” said Josh Chen, lead author of the study.
Hip implants with a delta ceramic or oxidised zirconium head and highly crosslinked polyethylene liner or cup had the lowest risk of revision during the 15 years after surgery, a new University of Bristol-led study has found. The research could help hospitals, surgeons and patients to choose what hip implant to use for replacement surgery.
The aim of the study, which appears in PLOS Medicine, was to establish hip implant materials at risk of revision. This would help orthopaedic surgeons, and patients, and to improve shared decision making before surgery by identifying hip implants with the lowest risk of revision.
The researchers analysed the UK’s National Joint Registry (NJR) data from 1 026 481 hip replacement patients carried out in the NHS and private sectors in England and Wales for up to 15 years after initial hip replacement operations (between 2003 to 2019).
After reviewing hip implants from the NJR data, the research team found the risk of revision following a hip replacement is influenced by the type of material used in the bearing surface. Bearing surfaces are the moving parts of an artificial hip joint that glide against each other during activity.
The data indicated that hip implants with a delta ceramic or oxidised zirconium head and highly crosslinked polyethylene liner or cup had the lowest risk of revision throughout the 15 years following hip replacement surgery.
These findings were confirmed when the research team investigated the specific reasons for revision hip replacements being performed. The data also showed 20 869 (2%) of hip replacement patients had to undergo revision after the initial surgery.
Senior author Dr Erik Lenguerrand, Senior Lecturer in Medical Statistics and Quantitative Epidemiologist in the Bristol Medical School:Translational Health Sciences (THS), said: “Our research has found the risk of hip replacement revision depends on the hip implant materials used in the original surgery. The lowest risk of revision are from implants with delta ceramic or oxidised zirconium head and a highly crosslinked polyethylene (HCLPE) liner or cup.
“Further research is needed to find out the association of implant materials with the risk of rehospitalisation, re-operation other than revision, mortality and the cost-effectiveness of these materials.”
Michael Whitehouse, Professor of Trauma and Orthopaedics at Bristol Medical School: THS, and senior clinical lead for the paper, explained: “Our study has used data from one of the largest registries in the world that includes all public and private health care sectors in England and Wales. This means that the data is more generally applicable than that available previously, which was limited by broad groupings of implant types or much smaller study size. It highlights the importance of considering the whole structure that is created when implants are put together to make up a hip replacement rather than focusing on individual components.
“Our findings will help hospitals, surgeons and patients to choose hip implants and combinations of them with the lowest risk of revision following an initial hip replacement operation.”
Tim Wilton, Medical Director of the National Joint Registry (NJR), added: “We are always delighted when the data from the NJR can be used by researchers to produce important research of this kind which gives meaningful analysis to guide surgeons and patients in their decisions. An important value of the NJR data is that it allows researchers a unique insight to assess the long-term performance of different hip implant materials.
“By tracking the combinations of materials used and subsequent revision rates, this research highlights the role of implant material choice in surgical outcomes. This ensures that the materials used can be optimised for longevity and patient health. Surgeons would be well advised to study these findings carefully in relation to the implant choices they make, and to use the information in pre-operative discussions with their patients. As the demand for joint replacements continues to rise, this insight can be invaluable in reducing revision surgery.”
The research was not a randomised controlled trial and therefore it was not possible to control all factors that can influence the risk of revision.
The categorisation of hip implants used as part of hip replacements is often broad in national joint replacement surgery registries and does not fully show differences in revision risks associated within the different types of implant materials grouped together.
Naked Prosthetics enables ‘life after amputation’ for 28-year-old Nelisiwe Nare
On the 18th of June 2020, a seemingly ordinary day at the office took a different turn for 28-year-old Nelisiwe Nare. At the time, Nare was based in the Northern Cape where she worked in the mining industry as a Process Engineer. That night, Nare’s hand got caught between a rotating drum and a lip plate of a magnetic separator. As a result of severe tissue damage, the ring and middle fingers on Nare’s right hand were amputated.
“When I awoke from surgery, the first thing I did was check my hand – only to realise that my fingers were no longer there,” says Nare. What followed was a long journey of healing, physical therapy and planning for the future.
Resilient and self-motivated, with a firm belief that anything is possible, Nare was determined to find a prosthetic that would enable her to return to as normal a life as possible. “My goal was to find a functional prosthetic. I was less concerned with hiding my injury or that my fingers had been amputated. My focus was on function, more than anything else.” This is why the usual aesthetic prosthetic hands that were on offer were not an option as they would not provide the functionality she was looking for.
At that time, there was nothing available on the local market that met Nare’s needs. After extensive research, she came across Naked Prosthetics – a provider of functional devices for partial hand and finger amputees. “Their devices were cool, functional, and unlike anything else I had seen. They aligned perfectly with the functional experience I was looking for.”
Nare was put in touch with her prosthetist who worked closely with Naked Prosthetics to understand the exact nature of Nare’s injury, type of amputation, her goals for the device and exactly how she hoped to use it. This included exact measurements and casting as well as being able to select her colour of choice.
“I remember the day I was able to collect my device,” continues Nare. That she was able to write on paper and type on a laptop on her very first use of the device was amazing and an experience in itself. “It’s a testament to how these devices are designed with movement, purpose and hand function in mind,” enthuses Nare.
“It allows me to do many of the things I used to do and is exactly what I had hoped for. As someone who spends a lot of time working on a laptop, the device has made a huge difference. Without it, my hand would very quickly tire, to the point where I’d feel like something was missing.”
Össur South Africa recently announced the availability of Naked Prosthetics to the local market. “The loss of a finger can be severely debilitating, impacting one’s ability to carry out seemingly ordinary yet essential everyday tasks – let alone the potential impact on one’s career and professional life,” says Dewald Grey, a Prosthetic Clinical Specialist with Össur South Africa. The resulting lack of mobility is also not limited to the area of amputation only, with many amputees experiencing a loss of mobility beyond the area of amputation. No fewer than 5% experience a resultant impairment of the entire body and as many as 75% of heavy manual labourers are unable to return to work.
“We aim to provide finger and partial-hand amputees with functional, high-quality solutions that seamlessly integrate into their lives and empower them to live a life without limitations – resuming employment and engaging in the activities they love,” says Grey.
“I believe prosthetics is one of the most evolving areas in the medical field,” Grey continues. “The use of 3D printing and precision engineering has led to highly advanced, functional prosthetic fingers. We also have different types of finger prosthetics for different needs – each one tailored precisely to the individual user’s amputation and specific hand structure.”
“I love my device. I’m grateful to have had the opportunity to access something that has shown me that amputation isn’t the end but, rather, a new beginning. Plus, I look super cool wearing it and it opens up opportunities for me to share my story and challenge stereotypes,” continues Nare. Her advice to anyone facing a similar injury, “no matter the extent of your amputation, it’s important to realise that life doesn’t stop when you lose your fingers.”
“Embrace what was and what’s to come, your amputation, scars, failures, stares and figuring it out! Embrace the ignorance, awkwardness and kindness. Most importantly of all, embrace the superhuman strength that comes with limb loss. My life before the amputation doesn’t compare to what it is now. I am more confident, I know there’s nothing I can’t do, and I am functional.”
Nare is currently exploring the land of the emirates while pursuing her Master of Management degree in Digital Business at Wits Business School.
The magnetic core of the nanodisc is magnetostrictive, which means it changes shape when magnetised. The rainbow nanodisc on the right is changing shape, allowing for the pink brain neuron to be stimulated. Image: Courtesy of the researchers
Novel magnetic nanodiscs could provide a much less invasive way of stimulating parts of the brain, paving the way for stimulation therapies without implants or genetic modification, MIT researchers report in Nature Nanotechnology.
The scientists envision that the tiny discs – about 250nm across – would be injected directly into the chosen brain location. From there, they could be activated at any time simply by applying an external magnetic field. The new particles could quickly find applications in biomedical research, and eventually, after sufficient testing, might be applied to clinical uses.
The research is described in the paper by Polina Anikeeva, a professor in MIT’s departments of Materials Science and Engineering and Brain and Cognitive Sciences, graduate student Ye Ji Kim, and 17 others at MIT and in Germany.
Deep brain stimulation (DBS) uses electrodes implanted in the target brain regions to treat symptoms of neurological and psychiatric conditions such as Parkinson’s disease and obsessive-compulsive disorder. Despite its efficacy, the surgical difficulty and clinical complications associated with DBS limit the number of cases where such an invasive procedure is warranted. The new nanodiscs could provide a much more benign way of achieving the same results.
Over the past decade other implant-free methods of producing brain stimulation have been developed, but were limited by spatial resolution or access. Other magnetic approaches studied needed genetic modifications to work, ruling it out for humans.
Since all nerve cells are sensitive to electrical signals, Kim, a graduate student in Anikeeva’s group, hypothesised that a magnetoelectric nanomaterial that can efficiently convert magnetisation into electrical potential could offer a path toward remote magnetic brain stimulation.
To this end, the researchers created nanodiscs with a magnetic core and piezolectric shell. When the core was squeezed by a magnetic field, strain in the shell produces a varying electrical polarisation. This enables the particles to deliver electrical pulses to neurons. The disc shape enhances the magnetostriction effect more than 1000-fold compared to spherical particles used previously.
After testing the nanodiscs with neurons in vitro, the researchers then injected small droplets of nanodisc-bearing solution into specific regions of the brains of mice. With an electromagnet, they turned on and off the stimulation in that region. That electrical stimulation “had an impact on neuron activity and on behaviour,” Kim says.
The team found that the magnetoelectric nanodiscs could stimulate a deep brain region, the ventral tegmental area, that is associated with feelings of reward.
The team also stimulated another brain area, the subthalamic nucleus, associated with motor control. “This is the region where electrodes typically get implanted to manage Parkinson’s disease,” Kim explains. The researchers were able to successfully demonstrate the modulation of motor control through the particles. Specifically, by injecting nanodiscs only in one hemisphere, the researchers could induce rotations in healthy mice by applying magnetic field.
The nanodiscs could trigger the neuronal activity comparable with conventional implanted electrodes delivering mild electrical stimulation. The authors achieved subsecond temporal precision for neural stimulation with their method yet observed significantly reduced foreign body responses as compared to the electrodes, potentially allowing for even safer deep brain stimulation.
The multilayered chemical composition and physical shape and size of the new multilayered nanodiscs is what made precise stimulation possible.
While the researchers successfully increased the magnetostrictive effect, the second part of the process, converting the magnetic effect into an electrical output, still needs more work, Anikeeva says. While the magnetic response was a thousand times greater, the conversion to an electric impulse was only four times greater than with conventional spherical particles.
“This massive enhancement of a thousand times didn’t completely translate into the magnetoelectric enhancement,” says Kim. “That’s where a lot of the future work will be focused, on making sure that the thousand times amplification in magnetostriction can be converted into a thousand times amplification in the magnetoelectric coupling.”
Further work is need before studies involving humans can begin, Kim says.
Deep brain stimulation (DBS) may provide immediate improvement in arm and hand strength and function weakened by traumatic brain injury or stroke, according to research from the University of Pittsburgh School of Medicine.
Encouraging results from extensive tests in monkeys and humans open a path for a new clinical application of an already widely used brain stimulation technology and offer insights into neural mechanisms underlying movement deficits caused by brain injury. The results are published in Nature Communications.
“Arm and hand paralysis significantly impacts the quality of life of millions of people worldwide,” said senior and corresponding author Elvira Pirondini, Ph.D., assistant professor of physical medicine and rehabilitation at Pitt. “Currently, we don’t have effective solutions for patients who suffered a stroke or traumatic brain injury but there is a growing interest in the use of neurotechnologies that stimulate the brain to improve upper-limb motor functions.”
Brain lesions caused by serious brain trauma or stroke can disrupt neural connections between the motor cortex, a key brain region essential for controlling voluntary movement, and the muscles. Weakening of these connections prevents effective activation of muscles and results in movement deficits, including partial or complete arm and hand paralysis.
To boost the activation of existing, but weakened, connections, researchers proposed to use deep brain stimulation (DBS), a surgical procedure that involves placing tiny electrodes in specific areas of the brain to deliver electrical impulses that regulate abnormal brain activity. Over the past several decades, DBS has revolutionised the treatment of neurological conditions such as Parkinson’s disease by providing a way to control symptoms that were once difficult to manage with medication alone.
“DBS has been life-changing for many patients. Now, thanks to ongoing advancements in the safety and precision of these devices, DBS is being explored as a promising option for helping stroke survivors recover their motor functions,” said senior author Jorge González-Martínez, MD, PhD, neurosurgery professor at Pitt. “It offers new hope to millions of people worldwide.”
Taking cues from another successful Pitt project that used electrical stimulation of the spinal cord to restore arm function in individuals affected by stroke, scientists hypothesised that stimulating the motor thalamus – a key relay hub of movement control – using DBS could help restore movements that are essential for tasks of daily living, such as object grasping. However, because the theory has not been tested before, they first had to test it in monkeys, which are the only animals that have the same organization of the connections between the motor cortex and the muscles as humans.
To understand the mechanism of how DBS of the motor thalamus helps improve voluntary arm movement and to finesse the specific location of the implant and the optimal stimulation frequency, researchers implanted the FDA-approved stimulation device into monkeys that had brain lesions affecting how effectively they could use their hands.
As soon as the stimulation was turned on, it significantly improved activation of muscles and grip force. Importantly, no involuntary movement was observed.
To verify that the procedure could benefit humans, the same stimulation parameters were used in a patient who was set to undergo DBS implantation into the motor thalamus to help with arm tremors caused by brain injury from a serious motor vehicle accident that resulted in severe paralysis in both arms.
As soon as the stimulation was turned on again, the range and strength of arm motion was immediately improved: The participant was able to lift a moderately heavy weight and reach, grasp and lift a drinking cup more efficiently and smoothly than without the stimulation.
To help bring this technology to more patients in the clinic, researchers are now working to test the long-term effects of DBS and determine whether chronic stimulation could further improve arm and hand function in individuals affected by traumatic brain injury or stroke.
Two new studies from UC San Francisco are pointing the way toward round-the-clock personalised care for people with Parkinson’s disease through an implanted device that can treat movement problems during the day and insomnia at night.
The approach, called adaptive deep brain stimulation, or aDBS, uses methods derived from AI to monitor a patient’s brain activity for changes in symptoms.
When it spots them, it intervenes with precisely calibrated pulses of electricity. The therapy complements the medications that Parkinson’s patients take to manage their symptoms, giving less stimulation when the drug is active, to ward off excess movements, and more stimulation as the drug wears off, to prevent stiffness.
It is the first time a so-called “closed loop” brain implant technology has been shown to work in Parkinson’s patients as they go about their daily lives. The device picks up brain signals to create a continuous feedback mechanism that can curtail symptoms as they arise. Users can switch out of the adaptive mode or turn the treatment off entirely with a hand-held device.
For the first study, researchers conducted a clinical trial with four people to test how well the approach worked during the day, comparing it to an earlier brain implant DBS technology known as constant or cDBS.
To ensure the treatment provided the maximum relief to each participant, the researchers asked them to identify their most bothersome symptom. The new technology reduced them by 50%. Results appear August 19 in Nature Medicine.
“There’s been a great deal of interest in improving DBS therapy by making it adaptive and self-regulating, but it’s only been recently that the right tools and methods have been available to allow people to use this long-term in their homes,” said Starr, who was recruited by UCSF in 1998 to start its DBS program.
Earlier this year, UCSF researchers led by Simon Little, MBBS, PhD, demonstrated in Nature Communications that adaptive DBS has the potential to alleviate the insomnia that plagues many patients with Parkinson’s.
“The big shift we’ve made with adaptive DBS is that we’re able to detect, in real time, where a patient is on the symptom spectrum and match it with the exact amount of stimulation they need,” said Little, associate professor of neurology and a senior author of both studies. Both Little and Starr are members of the UCSF Weill Institute for Neurosciences.
Restoring movement
Parkinson’s disease affects about 10 million people around the world. It arises from the loss of dopamine-producing neurons in deep regions of the brain that are responsible for controlling movement. The lack of those cells can also cause non-motor symptoms, affecting mood, motivation and sleep.
Treatment usually begins with levodopa, a drug that replaces the dopamine these cells are no longer able to make. However, excess dopamine in the brain as the drug takes effect can cause uncontrolled movements, called dyskinesia. As the medication wears off, tremor and stiffness set in again.
Some patients then opt to have a standard cDBS device implanted, which provides a constant level of electrical stimulation. Constant DBS may reduce the amount of medication needed and partially reduce swings in symptoms. But the device also can over- or undercompensate, causing symptoms to veer from one extreme to the other during the day.
Closing the loop
To develop a DBS system that could adapt to a person’s changing dopamine levels, Starr and Little needed to make the DBS capable of recognising the brain signals that accompany different symptoms.
Previous research had identified patterns of brain activity related to those symptoms in the subthalamic nucleus, or STN, the deep brain region that coordinates movement. This is the same area that cDBS stimulates, and Starr suspected that stimulation would mute the signals they needed to pick up.
So, he found alternative signals elsewhere in the brain – the motor cortex – that wouldn’t be weakened by the DBS stimulation.
The next challenge was to work out how to develop a system that could use these dynamic signals to control DBS in an environment outside the lab.
Building on findings from adaptive DBS studies that he had run at Oxford University a decade earlier, Little worked with Starr and the team to develop an approach for detecting these highly variable signals across different medication and stimulation levels.
Over the course of many months, postdoctoral scholars Carina Oerhn, PhD, Lauren Hammer, PhD, and Stephanie Cernera, PhD, created a data analysis pipeline that could turn all of this into personalised algorithms to record, analyse and respond to the unique brain activity associated with each patient’s symptom state.
John Ngai, PhD, who directs the Brain Research Through Advancing Innovative Neurotechnologies® initiative (The BRAIN Initiative®) at the National Institutes of Health, said the study promises a marked improvement over current Parkinson’s treatment.
“This personalised, adaptive DBS embodies The BRAIN Initiative’s core mission to revolutionise our understanding of the human brain,” he said.
A better night’s sleep
Continuous DBS is aimed at mitigating daytime movement symptoms and doesn’t usually alleviate insomnia.
But in the last decade, there has been a growing recognition of the impact that insomnia, mood disorders and memory problems have on Parkinson’s patients.
To help fill that gap, Little conducted a separate trial that included four patients with Parkinson’s and one patient with dystonia, a related movement disorder. In their paper published in Nature Communications, first author Fahim Anjum, PhD, a postdoctoral scholar in the Department of Neurology at UCSF, demonstrated that the device could recognise brain activity associated with various states of sleep. He also showed it could recognise other patterns that indicate a person is likely to wake up in the middle of the night.
Little and Starr’s research teams, including their graduate student Clay Smyth, have started testing new algorithms to help people sleep. Their first sleep aDBS study was published last year in Brain Stimulation.
Scientists are now developing similar closed-loop DBS treatments for a range of neurological disorders.
“We see that it has a profound impact on patients, with potential not just in Parkinson’s but probably for psychiatric conditions like depression and obsessive-compulsive disorder as well,” Starr said. “We’re at the beginning of a new era of neurostimulation therapies.”
Osteomyelitis from Staphylococcus Aureus infection. Credit: Scientific Animations CC0
In patients who have undergone knee or hip replacement surgery, clinicians are noticing increasing numbers of chronic bone infections linked to a bacterial strain commonly found on the skin. A new study published in the Journal of Orthopaedic Research provides insights into the mechanisms involved, and how the bacteria lingers in bone reservoirs.
Utilising mouse models of bone infection and systematic electron microscopy studies, scientists found that the common skin bacteria Cutibacterium acnes can persist as layers of biofilms for weeks on contaminated titanium or stainless-steel implants. In mice, C. acnes could persist for 28 days in the tibia, and the researchers also observed C. acnes spreading to internal organs. compared to Staphylococcus aureus infections, C. acnes chronic osteomyelitis revealed markedly reduced bone osteolysis and abscess formation.
C. acnes can also invade deep pockets of the bone called osteocyte lacuno-canalicular networks and persist there.
“Our study highlights that osteocyte lacuno-canalicular networks can be a major reservoir for this bacterium and potentially provides a novel mechanism of why Cutibacterium acnes chronic bone infections are difficult to treat in the clinic,” said corresponding author Gowrishankar Muthukrishnan, PhD, of the University of Rochester Medical Center.
