Creating a ‘Window to the Brain’

A team of University of California, Riverside researchers have developed a novel transparent skull implant that literally provides a “window to the brain”, which they hope will eventually open new treatment options for patients with life-threatening neurological disorders, such as brain cancer and traumatic brain injury.

The team’s implant is made of the same ceramic material currently used in hip implants and dental crowns, yttria-stabilized zirconia (YSZ). However, the key difference is that their material has been processed in a unique way to make it transparent.

Since YSZ has already proven itself to be well-tolerated by the body in other applications, the team’s advancement now allows use of YSZ as a permanent window through which doctors can aim laser-based treatments for the brain, importantly, without having to perform repeated craniectomies, which involve removing a portion of the skull to access the brain.

The work also dovetails with President Obama’s recently-announced BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative, which aims to revolutionize the understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders. The team envisions potential for their YSZ windows to facilitate the clinical translation of promising brain imaging and neuromodulation technologies being developed under this initiative.

“This is a case of a science fiction sounding idea becoming science fact, with strong potential for positive impact on patients,” said Guillermo Aguilar, a professor of mechanical engineering at UC Riverside’s Bourns College of Engineering (BCOE).

Aguilar is part of 10-person team, comprised of faculty, graduate students and researchers from UC Riverside’s Bourns College of Engineering and School of Medicine, who recently published a paper “Transparent Nanocrystalline Yttria-Stabilized-Zirconia Calvarium Prosthesis”  about their findings online in the journal Nanomedicine: Nanotechnology, Biology and Medicine.

Laser-based treatments have shown significant promise for many brain disorders. However, realization of this promise has been constrained by the need for performing a craniectomy to access the brain since most medical lasers are unable to penetrate the skull. The transparent YSZ implants developed by the UC Riverside team address this issue by providing a permanently implanted view port through the skull.

“This is a crucial first step towards an innovative new concept that would provide a clinically-viable means for optically accessing the brain, on-demand, over large areas, and on a chronically-recurring basis, without need for repeated craniectomies,” said team member Dr. Devin Binder, a clinician and an associate professor of biomedical sciences at UC Riverside.

Although the team’s YSZ windows are not the first transparent skull implants to be reported, they are the first that could be conceivably used in humans, which is a crucial distinction. This is due to the inherent toughness of YSZ, which makes it far more resistant to shock and impact than the glass-based implants previously demonstrated by others. This not only enhances safety, but it may also reduce patient self-consciousness, since the reduced vulnerability of the implant could minimize the need for conspicuous protective headgear.

Brain research shows psychopathic criminals do not lack empathy, but fail to use it automatically

Criminal psychopathy can be both repulsive and fascinating, as illustrated by the vast number of books and movies inspired by this topic. Offenders diagnosed with psychopathy pose a significant threat to society, because they are more likely to harm other individuals and to do so again after being released. A brain imaging study in the Netherlands shows individuals with psychopathy have reduced empathy while witnessing the pains of others. When asked to empathize, however, they can activate their empathy. This could explain why psychopathic individuals can be callous and socially cunning at the same time.

Why are psychopathic individuals more likely to hurt others? Individuals with psychopathy characteristically demonstrate reduced empathy with the feelings of others, which may explain why it is easier for them to hurt other people. However, what causes this lack of empathy is poorly understood. Scientific studies on psychopathic subjects are notoriously hard to conduct. “Convicted criminals with a diagnosis of psychopathy are confined to high-security forensic institutions in which state-of-the-art technology to study their brain, like magnetic resonance imaging, is usually unavailable”, explains Professor Christian Keysers, Head of the Social Brain Lab in Amsterdam, and senior author of a study on psychopathy appearing in the Journal Brain this week. “Bringing them to scientific research centres, on the other hand, requires the kind of high-security transportation that most judicial systems are unwilling to finance.”

The Dutch judicial system, however, seems to be an exception. They joined forces with academia to promote a better understanding of psychopathy. As a result, criminals with psychopathy were transported to the Social Brain Lab of the University Medical Center in Groningen (The Netherlands). There, the team could use state of the art high-field functional magnetic resonance imaging to peak into the brain of criminals with psychopathy while they view the emotions of others.

The study, which will appear on the 25th of July in the journal Brain (published by Oxford University Press) and is entitled “Reduced spontaneous but relatively normal deliberate vicarious representations in psychopathy”, included 18 individuals with psychopathy and a control group, and consisted of three parts. “All participants first watched short movie clips of two people interacting with each other, zoomed in on their hands. The movie clips showed one hand touching the other in a loving, a painful, a socially rejecting or a neutral way. At this stage, we asked them to look at these movies just as they would watch one of their favourite films”, Harma Meffert, the first author of the paper, explains. Meffert was a graduate student in the Social Brain Lab while the study was conducted, and is now a post-doctoral fellow at the National Institutes of Mental Health in Bethesda.

Next, the participants watched the same clips again. This time, however, the researchers prompted them explicitly to “empathise with one of the actors in the movie”, that is, they were requested to really try to feel what the actors in the movie were feeling.

"In the third and final part, we performed similar hand interactions with the participants themselves, while they were lying in the scanner, having their brain activity measured", adds Meffert. "We wanted to know to what extent they would activate the same brain regions while they were watching the hand interactions in the movies, as they would when they were experiencing these same hand interactions themselves."

Our brains are equipped with what scientists call a “mirror system”. For example, the motor cortex of the brain normally allows you to move your own body. Your so called somatosensory cortex, when activated, makes you to feel touch on your skin. Your insula, finally, when activated makes you feel emotions like pain or disgust. In the last decades, brain scientists have discovered that when people watch other people move their body, or see those people being touched, or have emotions, these same brain regions are activated. In other words, the actions, touch or emotions of others become your own. This “mirror system” possibly constitutes a crucial part of our ability to empathize with other people, and it has been previously shown, that the less you activate this system, the less you report to empathize with other people. It has been suggested that individuals with psychopathy might somehow suffer from a broken “mirror system”, resulting in a diminished ability to empathize with their victims.

As it turns out, however, the picture seems to be more complex. When asked to just watch the film clips, the individuals with psychopathy indeed did activate their mirror system less. “Regions involved in their own actions, emotions and sensations were less active than that of controls while they saw what happens in others”, summarizes Christian Keysers. “At first, this seems to suggest that psychopathic criminals might hurt others more easily than we do, because they do not feel pain, when they see the pain of their victims.”

As the second part of the study revealed, however, it’s not quite so simple. Instead of generally activating their mirror system less, individuals with psychopathy rather seem not to use this system spontaneously, but they can use it when asked to. “When explicitly asked to empathize, the differences between how strongly the individuals with and without psychopathy activate their own actions, sensations and emotions almost entirely disappeared in their empathic brain”, explains Valeria Gazzola, Assistant Professor at the UMCG and second author of the paper. “Psychopathy may not be so much the incapacity to empathize, but a reduced propensity to empathize, paired with a preserved capacity to empathize when required to do so”. The brain data suggests, that by default, psychopathic individuals feel less empathy than others. If they try to empathize, however, they can switch to ‘empathy mode’.

There might be two sides to these findings. The darker side is that reduced spontaneous empathy together with a preserved capacity for empathy might be the cocktail that makes these individuals so callous when harming their victims and at the same time so socially cunning when they try to seduce their victims. Whether individuals with psychopathy autonomously switch their empathy mode on and off depending on the requirements of a social situation however remains to be established. The brighter side is that the preserved capacity for empathy might be harnessed in therapy. Instead of having to create a capacity for empathy, therapies may need to focus on making the existing capacity more automatic to prevent them from further harming others. How to do so, remains at this stage uncertain.

Stress Test and Brain Scans Pinpoint Two Distinct Forms of Gulf War Illness

Researchers at Georgetown University Medical Center say their new work suggests that Gulf War illness may have two distinct forms depending on which brain regions have atrophied. Their study of Gulf War veterans, published online today in PLOS ONE, may help explain why clinicians have consistently encountered veterans with different symptoms and complaints.

Using brain imaging that was acquired before and after exercise tests, the researchers studied the effects of physical stress on the veterans and controls. Following exercise, subgroups were evident. In 18 veterans, they found that pain levels increased after completion of the exercise stress tests exercised; fMRI scans in these participants showed loss of brain matter in adjacent regions associated with pain regulation.  

During cognitive tasks, this group showed an increased use of the basal ganglia — a potential compensatory strategy the brain uses that is also seen in neurodegenerative disorders such as Alzheimer’s disease. Following exercise, this group lost the ability to employ their basal ganglia, suggesting an adverse response to a physiological stressor.

In addition, “a separate group of 10 veterans had a very different clinical alteration,” says lead author Rakib Rayhan, a researcher in the lab of the study’s senior investigator, James Baraniuk, MD, a professor of medicine at GUMC.

In these 10 veterans, the researchers found substantial increases in heart rate. They also discovered that this subgroup had atrophy in the brain stem, which regulates heart rate. .

In addition, brain scans during a cognitive task performed prior to exercise showed increased compensatory use of the cerebellum, again a trait seen in neurodegenerative disorders. Like the other group, this cohort lost the ability to use this compensatory area after exercise.

Alterations in cognition, brain structure and exercise-induced symptoms found in the veterans were absent in the 10-participant matched control group, the researchers say.

“The use of other brain areas to compensate for a damaged area is seen in other disorders, such as Alzheimer’s disease, which is why we believe our data show that these veterans are suffering from central nervous system dysfunction,” Rayhan explains. He adds, however, that because such changes are similar to other neurodegenerative states, it doesn’t mean that veterans will progress to Alzheimer’s or other diseases.

These findings — a surprise to researchers — follow a study in Gulf War veterans published in March in PLOS ONE that reported abnormalities in the bundle of nerve fibers connecting the brain areas involved in the processing and perception of pain and fatigue.

Gulf War Illness is the mysterious malady believed to have affected more than 200,000 military personnel who served in the 1990-1991 Operation Desert Shield and Desert Storm.

Although veterans were exposed to nerve agents, pesticides and herbicides (among other toxic chemicals), no one has definitively linked any single exposure or underlying mechanism to Gulf War illness.

The symptoms of Gulf War illness — which have not been widely accepted by the public or medical professionals — range from mild to debilitating and can include widespread pain, fatigue and headache, as well as cognitive and gastrointestinal dysfunctions.

“Our findings help explain and validate what these veterans have long said about their illness,” Rayhan says.

Incredible Technology: How to See Inside the Mind

Human experience is defined by the brain, yet much about this 3-lb. organ remains a mystery. Even so, from brain imaging to brain-computer interfaces, scientists have made impressive strides in developing technologies to peer inside the mind.

Imaging the brain

Currently, scientists who study the brain can look at its structure or its function. In structural imaging, machines take snapshots of the brain’s large-scale anatomy that can be used to diagnose tumors or blood clots, for example. Functional imaging provides a dynamic view of the brain, showing which areas are active during thinking and perception.

Structural-imaging techniques include CAT scans, or computerized axial tomography, which takes images of slices through the brain by beaming X-rays at the head from many different angles. CAT, or CT, scans are often used to diagnose a brain injury, for example. Another method, positron emission tomography (PET), generates both 2D and 3D images of the brain: A radioactively labeled chemical injected into the blood emits gamma rays that a scanner detects. And magnetic resonance imaging (MRI) provides a view of the brain’s overall structure by measuring the magnetic spin of atoms inside a strong magnetic field.

"There’s no question that MRI is probably the best way to see the brain," said Dr. Mauricio Castillo, a radiologist at the University of North Carolina at Chapel Hill and editor-in-chief of the American Journal of Neuroradiology.

In the realm of functional imaging, the current gold standard is functional MRI (fMRI). This technique measures changes in blood flow to different brain areas as a proxy for which areas are active when someone performs a task like reading a word or viewing a picture.

"The emphasis nowadays is to try to merge how the brain is wired with the activation of the cortex [the brain’s outermost layer]," Castillo said.

Several methods can be combined to merge brain structure and function. For example, MRI and PET scanning can be performed simultaneously, and the images can be combined to show physiological activity superimposed on an anatomical map of the brain. The end result can be used to tell a surgeon the location of a brain lesion so it can be removed, Castillo said.

Recently, a new technique has been developed to literally see inside the brain. Called CLARITY (originally for Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging/Immunostaining/In situ hybridization-compatible Tissue-hYdrogel), it can make a (nonliving) brain transparent to light while keeping its structure intact. The technique has already been used to visualize the neurological wiring of an adult mouse brain.

Decoding thoughts

Some scientists want to see inside the brain more figuratively. Enter brain-computer interfaces (BCIs or BMIs, brain-machine interfaces), devices that connect brain signals to an external device, such as a computer or prosthetic limb. BCIs range from noninvasive systems that consist of electrodes placed on the scalp, to more invasive ones that require the electrodes to be implanted in the brain itself.

Noninvasive BCIs include scalp-based electroencephalography (EEG), which records the activity of many neurons over large brain areas. The advantage of EEG-based systems is that they don’t require surgery. On the other hand, these systems can only detect generalized brain activity, so the user must focus his or her thoughts on just a single task.

More invasive systems include electrocorticography (ECoG), in which electrodes are implanted on the surface of the brain to record EEG signals from the cortex. Since Wilder Penfield and Herbert Jasper pioneered the technique in the early 1950s, it has been used, among other purposes, to identify brain regions where epileptic seizures begin.

Some BCIs use electrodes implanted inside the brain’s cortex. Although these systems are more invasive, they have much better resolution and can pick up the signals sent by individual neurons. BCIs can now even allow humans with paraplegia (paralysis of all four limbs) to control a robotic arm through thought alone, or allow users to spell out words on a computer screen using just their mind.

Despite many advances, a lot remains unknown about the brain. To bridge this gap, American scientists are embarking on a new project to map the human brain, announced by President Barack Obama in April, called the BRAIN initiative (Brain Research through Advancing Innovative Neurotechnologies).

But neuroscientists have their work cut out for them. “The brain is probably the most complex machine in the universe,” Castillo said. “We’re still a long way from understanding it.”

‘Brainbow,’ version 2.0: Researchers refine breakthrough system for producing images of brain, nervous system

The breakthrough technique that allowed scientists to obtain one-of-a-kind, colorful images of the myriad connections in the brain and nervous system is about to get a significant upgrade.

A group of Harvard researchers, led by Joshua Sanes, the Jeff C. Tarr Professor of Molecular and Cellular Biology and Paul J. Finnegan Family Director, Center for Brain Science, and Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology and Santíago Ramón y Cajal Professor of Arts and Sciences, has made a host of technical improvements in the “Brainbow” imaging technique. Their work is described in a May 5 paper in Nature Methods.

First described in 2007, the system combines three fluorescent proteins — one red, one blue, and one green — to label different cells with as many as 90 colors. By studying the resulting images, researchers were able to begin to understand how the millions of neurons in the brain are connected.

“‘Brainbow’ generated beautiful images of a kind we had never been able to obtain before, but it was difficult in some ways,” said Sanes, who also serves as director of the Center for Brain Science.

“These modifications aim to overcome some of the more problematic features of the original genetic constructs,” Lichtman said. “Lead author Dawen Cai, a research associate in our labs, worked hard and creatively to find ways to make the ‘Brainbow’ colors brighter, more variable, and useable in situations where the original gene constructs were hard to implement. Our first look at these animals suggests that these improvements are fantastic.”

Among the challenges faced by researchers using the original method, Sanes said, was the chance that certain colored proteins would bleach out faster than others.

“If one color bleaches faster than the others, you start with a ‘Brainbow,’ but by the time you’re done imaging, you might just have a ‘blue-bow,’ because the red and yellow bleach too fast,” he said.

Sanes said that some colors also were too dim, causing problems in the imaging process, while in other cases the protein didn’t fill the whole neuron evenly enough, or there was an overabundance of a certain color in an image.

“What we decided to do was to make the next generation of ‘Brainbow,’” Sanes said. “We systematically set out to look at these problems. We looked at a whole range of fluorescent proteins to find the ones that were brightest and wouldn’t bleach as much, and we developed new transgenic methods to avoid the predominance of a particular color.”

The researchers also explored new ways to create “Brainbow” images, including using viruses to introduce fluorescent proteins into cells.

The advantage of the new technique, Sanes said, is it offers researchers the chance to target certain parts of the brain and better understand how neurons radiate out to connect with other brain regions. Ultimately, he said, he hopes that other researchers are able to apply the techniques outlined in the paper in the same way that they expanded on the first “Brainbow” method.

“People adapted the method to study a number of interesting questions in other tissues to examine cellular relationships and cell lineages in kidney and skin cells,” he said. “It was also used to examine the nervous system in animals like zebrafish and C. elegans. With these new tools, I think we’ve taken the next step.”