Neuroscience

A team of neuroengineers based at Brown University has developed a fully implantable and rechargeable wireless brain sensor capable of relaying real-time broadband signals from up to 100 neurons in freely moving subjects. Several copies of the novel low-power device, described in the Journal of Neural Engineering, have been performing well in animal models for more than year, a first in the brain-computer interface field. Brain-computer interfaces could help people with severe paralysis control devices with their thoughts.

Arto Nurmikko, professor of engineering at Brown University who oversaw the device’s invention, is presenting it this week at the 2013 International Workshop on Clinical Brain-Machine Interface Systems in Houston.

“This has features that are somewhat akin to a cell phone, except the conversation that is being sent out is the brain talking wirelessly,” Nurmikko said.

Neuroscientists can use such a device to observe, record, and analyze the signals emitted by scores of neurons in particular parts of the animal model’s brain.

Meanwhile, wired systems using similar implantable sensing electrodes are being investigated in brain-computer interface research to assess the feasibility of people with severe paralysis moving assistive devices like robotic arms or computer cursors by thinking about moving their arms and hands.

This wireless system addresses a major need for the next step in providing a practical brain-computer interface,” said neuroscientist John Donoghue, the Wriston Professor of Neuroscience at Brown University and director of the Brown Institute for Brain Science.

Tightly packed technology

In the device, a pill-sized chip of electrodes implanted on the cortex sends signals through uniquely designed electrical connections into the device’s laser-welded, hermetically sealed titanium “can.” The can measures 2.2 inches (56 mm) long, 1.65 inches (42 mm) wide, and 0.35 inches (9 mm) thick. That small volume houses an entire signal processing system: a lithium ion battery, ultralow-power integrated circuits designed at Brown for signal processing and conversion, wireless radio and infrared transmitters, and a copper coil for recharging — a “brain radio.” All the wireless and charging signals pass through an electromagnetically transparent sapphire window.

In all, the device looks like a miniature sardine can with a porthole.

But what the team has packed inside makes it a major advance among brain-machine interfaces, said lead author David Borton, a former Brown graduate student and postdoctoral research associate who is now at Ecole Polytechnique Federale Lausanne in Switzerland.

“What makes the achievement discussed in this paper unique is how it integrated many individual innovations into a complete system with potential for neuroscientific gain greater than the sum of its parts,” Borton said. “Most importantly, we show the first fully implanted microsystem operated wirelessly for more than 12 months in large animal models — a milestone for potential [human] clinical translation.”

The device transmits data at 24 Mbps via 3.2 and 3.8 Ghz microwave frequencies to an external receiver. After a two-hour charge, delivered wirelessly through the scalp via induction, it can operate for more than six hours.

“The device uses less than 100 milliwatts of power, a key figure of merit,” Nurmikko said.

Co-author Ming Yin, a Brown postdoctoral scholar and electrical engineer, said one of the major challenges that the team overcame in building the device was optimizing its performance given the requirements that the implant device be small, low-power and leak-proof, potentially for decades.

“We tried to make the best tradeoff between the critical specifications of the device, such as power consumption, noise performance, wireless bandwidth and operational range,” Yin said. “Another major challenge we encountered was to integrate and assemble all the electronics of the device into a miniaturized package that provides long-term hermeticity (water-proofing) and biocompatibility as well as transparency to the wireless data, power, and on-off switch signals.”

With early contributions by electrical engineer William Patterson at Brown, Yin helped to design the custom chips for converting neural signals into digital data. The conversion has to be done within the device, because brain signals are not produced in the ones and zeros of computer data.

Ample applications

The team worked closely with neurosurgeons to implant the device in three pigs and three rhesus macaque monkeys. The research in these six animals has been helping scientists better observe complex neural signals for as long as 16 months so far. In the new paper, the team shows some of the rich neural signals they have been able to record in the lab. Ultimately this could translate to significant advances that can also inform human neuroscience.

Current wired systems constrain the actions of research subjects, Nurmikko said. The value of wireless transmission is that it frees subjects to move however they intend, allowing them to produce a wider variety of more realistic behaviors. If neuroscientists want to observe the brain signals produced during some running or foraging behaviors, for instance, they can’t use a cabled sensor to study how neural circuits would form those plans for action and execution or strategize in decision making.

In the experiments in the new paper, the device is connected to one array of 100 cortical electrodes, the microscale individual neural listening posts, but the new device design allows for multiple arrays to be connected, Nurmikko said. That would allow scientists to observe ensembles of neurons in multiple related areas of a brain network.

The new wireless device is not approved for use in humans and is not used in clinical trials of brain-computer interfaces. It was designed, however, with that translational motivation.

“This was conceived very much in concert with the larger BrainGate* team, including neurosurgeons and neurologists giving us advice as to what were appropriate strategies for eventual clinical applications,” said Nurmikko, who is also affiliated with the Brown Institute for Brain Science.

Borton is now spearheading the development of a collaboration between EPFL and Brown to use a version of the device to study the role of the motor cortex in an animal model of Parkinson’s disease.

Meanwhile the Brown team is continuing work on advancing the device for even larger amounts of neural data transmission, reducing its size even further, and improving other aspects of the device’s safety and reliability so that it can someday be considered for clinical application in people with movement disabilities.

Fresh insights into the protective seal that surrounds the DNA of our cells could help develop treatments for inherited muscle, brain, bone and skin disorders.

Researchers have discovered that the proteins within this coating – known as the nuclear envelope – vary greatly between cells in different organs of the body.

This variation means that certain disease causing proteins will interact with the proteins in the protective seal to cause illness in some organs, but not others.

Until now scientists had thought that all proteins within the nuclear envelope were the same in every type of organ.

In particular the finding may provide insights into a rare muscle disease, Emery-Dreifuss muscular dystrophy.

This condition causes muscle wastage and heart problems, affects only muscles, even though it is caused by a defect in a nuclear envelope protein found in every cell in the body.

Scientists say that the envelope proteins they have identified as being specific to muscle may interact with the defective nuclear envelope protein that causes Emery-Dreifuss muscular dystrophy, to give rise to the disease.

In a similar way, this may help to explain other heritable diseases that only affect certain parts of the body despite the defective proteins being present in every cell. The study also identified nuclear envelope proteins specific to liver and blood.

Some of these also interact with proteins in all cells that are responsible for other nuclear envelope diseases, ranging from brain and fat to skin diseases, and so may help explain why things go wrong.

Dr Eric Schirmer, of the University of Edinburgh’s Wellcome Trust Centre for Cell Biology, who led the study said: “Nobody could have imagined what we found.

The fact that most proteins in the nuclear envelope would be specific for certain tissue types is a very exciting development. This may finally enable us to understand this ever-growing spectrum of inherited diseases as well as new aspects of tissue-specific gene regulation.”

The findings build on previous research that showed proteins in the nuclear envelope are linked to more than 20 heritable diseases.

In a recently published study in the journal Biological Trace Element Research, Arizona State University researchers report that children with autism had higher levels of several toxic metals in their blood and urine compared to typical children. The study involved 55 children with autism ages 5–16 years compared to 44 controls of similar age and gender.

The autism group had significantly higher levels of lead in their red blood cells (+41 percent) and significantly higher urinary levels of lead (+74 percent), thallium (+77 percent), tin (+115 percent), and tungsten (+44 percent).  Lead, thallium, tin, and tungsten are toxic metals that  can impair brain development and function, and also interfere with the normal functioning of other body organs and systems.

A statistical analysis was conducted to determine if the levels of toxic metals were associated with autism severity, using three different scales of autism severity. It was found that 38-47 percent of the variation of autism severity was associated with the level of several toxic metals, with cadmium and mercury being the most strongly associated.

In the paper about the study, the authors state “We hypothesize that reducing early exposure to toxic metals may help ameliorate symptoms of autism, and treatment to remove toxic metals may reduce symptoms of autism; these hypotheses need further exploration, as there is a growing body of research to support it.”

The study was led by James Adams, a President’s Professor in the School for Engineering of Matter, Transport and Energy, one of ASU’s Ira A. Fulton Schools of Engineering. He directs the ASU Autism/Asperger’s Research Program.

Adams previously published a study on the use of DMSA, an FDA-approved medication for removing toxic metals. The open-label study found that DMSA was generally safe and effective at removing some toxic metals. It also found that DMSA therapy improved some symptoms of autism. The biggest improvement was for children with the highest levels of toxic metals in their urine.

Overall, children with autism have higher average levels of several toxic metals, and levels of several toxic metals are strongly associated with variations in the severity of autism for all three of the autism severity scales investigated.

(Image: Matthias Kulka / Corbis)

The origin of an innate ability the brain has to protect itself from damage that occurs in stroke has been explained for the first time.

The Oxford University researchers hope that harnessing this inbuilt biological mechanism, identified in rats, could help in treating stroke and preventing other neurodegenerative diseases in the future.

'We have shown for the first time that the brain has mechanisms that it can use to protect itself and keep brain cells alive,' says Professor Alastair Buchan, Head of the Medical Sciences Division and Dean of the Medical School at Oxford University, who led the work.

The researchers report their findings in the journal Nature Medicine and were funded by the UK Medical Research Council and National Institute for Health Research.

Stroke is the third most common cause of death in the UK. Every year around 150,000 people in the UK have a stroke.

It occurs when the blood supply to part of the brain is cut off. When this happens, brain cells are deprived of the oxygen and nutrients they need to function properly, and they begin to die.

'Time is brain, and the clock has started immediately after the onset of a stroke. Cells will start to die somewhere from minutes to at most 1 or 2 hours after the stroke,' says Professor Buchan.

This explains why treatment for stroke is so dependent on speed. The faster someone can reach hospital, be scanned and have drugs administered to dissolve any blood clot and get the blood flow re-started, the less damage to brain cells there will be.

It has also motivated a so-far unsuccessful search for ‘neuroprotectants’: drugs that can buy time and help the brain cells, or neurons, cope with damage and recover afterwards.

The Oxford University research group have now identified the first example of the brain having its own built-in form of neuroprotection, so-called ‘endogenous neuroprotection’.

They did this by going back to an observation first made over 85 years ago. It has been known since 1926 that neurons in one area of the hippocampus, the part of the brain that controls memory, are able to survive being starved of oxygen, while others in a different area of the hippocampus die. But what protected that one set of cells from damage had remained a puzzle until now.

'Previous studies have focused on understanding how cells die after being depleted of oxygen and glucose. We considered a more direct approach by investigating the endogenous mechanisms that have evolved to make these cells in the hippocampus resistant,' explains first author Dr Michalis Papadakis, Scientific Director of the Laboratory of Cerebral Ischaemia at Oxford University.

Working in rats, the researchers found that production of a specific protein called hamartin allowed the cells to survive being starved of oxygen and glucose, as would happen after a stroke.

They showed that the neurons die in the other part of the hippocampus because of a lack of the hamartin response.

The team was then able to show that stimulating production of hamartin offered greater protection for the neurons.

Professor Buchan says: ‘This is causally related to cell survival. If we block hamartin, the neurons die when blood flow is stopped. If we put hamartin back, the cells survive once more.’

Finally, the researchers were able to identify the biological pathway through which hamartin acts to enable the nerve cells to cope with damage when starved of energy and oxygen.

The group points out that knowing the natural biological mechanism that leads to neuroprotection opens up the possibility of developing drugs that mimic hamartin’s effect.

Professor Buchan says: ‘There is a great deal of work ahead if this is to be translated into the clinic, but we now have a neuroprotective strategy for the first time. Our next steps will be to see if we can find small molecule drug candidates that mimic what hamartin does and keep brain cells alive.

'While we are focussing on stroke, neuroprotective drugs may also be of interest in other conditions that see early death of brain cells including Alzheimer's and motor neurone disease,' he suggests.